HK1148273B - Anti-infective pyrimidines and uses thereof - Google Patents

Description

Anti-infective pyrimidines and uses thereof

Cross reference to related patent applications

This patent application claims priority from U.S. provisional patent application No.60/972,881 (filed on 9/17/2007) and U.S. provisional patent application No.61/096,792 (filed on 9/13/2008). Both provisional patent applications are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to: (a) particularly useful as inhibitors of Hepatitis C Virus (HCV) and salts thereof; (b) intermediates useful in the preparation of the compounds and salts; (c) compositions containing said compounds and salts; (d) processes for preparing said intermediates, compounds, salts and compositions; (e) methods of use of the compounds, salts, and compositions; and (f) kits comprising the compounds, salts, and compositions.

Background

Hepatitis c is a blood-borne, infectious viral disease caused by a hepatotrophic virus called HCV. At least 6 different HCV genotypes (several subtypes per genotype) are known to date. In north america, HCV genotype 1a predominates, followed by HCV genotypes 1b, 2a, 2b, and 3 a. In the united states, HCV genotypes 1, 2 and 3 are the most common, with about 80% of hepatitis c patients bearing HCV genotype 1. In europe HCV genotype 1b predominates, followed by HCV genotypes 2a, 2b, 2c and 3 a. HCV genotypes 4 and 5 were found almost exclusively in africa. As discussed below, the HCV genotype of a patient is clinically important in determining the potential response of the patient to treatment and the time required for such treatment.

HCV infection can lead to liver inflammation (hepatitis), usually asymptomatic, but the accompanying chronic hepatitis can lead to cirrhosis (scarring of liver fibrosis), liver cancer and/or liver failure. According to the world health organization, there are about 170,000,000 people chronically infected with HCV worldwide, and about 3,000,000 to about 4,000,000 people newly infected with HCV worldwide every year. It has been reported by the U.S. centers for disease control and prevention that about 4,000,000 people in the U.S. are infected with HCV. Co-infection with Human Immunodeficiency Virus (HIV) is a common phenomenon, with a higher rate of HCV infection among HIV positive populations.

Spontaneous viral clearance is less likely, but most patients with chronic hepatitis c do not clear the virus when untreated. Indications for treatment generally include confirmation of HCV infection and persistent abnormalities in liver function tests. There are two main treatment regimens for the treatment of hepatitis c: monotherapy (using an interferon agent- "conventional" or long-acting pegylated interferon) and combination therapy (using an interferon agent and ribavirin). Interferon injected into the blood works by boosting the immune response to HCV; ribavirin, which is administered orally, is thought to act by preventing HCV replication. Ribavirin alone is not effective in inhibiting HCV levels, but the interferon/ribavirin combination is more effective than interferon alone. Typically, depending on the HCV genotype, a combination of peginterferon alfa and ribavirin is used to treat hepatitis c for 24 or 48 weeks.

The aim of the treatment is to sustain the viral response, i.e. no measurable HCV is present in the blood after the treatment is completed. After the combination treatment with peginterferon alfa and ribavirin, the sustained cure rate (sustained viral response) was about 75% or greater for 24 weeks of treatment for HCV genotype 2 and 3 populations, about 50% for 48 weeks of treatment for HCV genotype 1 population, and about 65% for 48 weeks of treatment for HCV genotype 4 population.

Treatment may be performed on a practical basis, particularly for patients with a history prior to drug or alcohol abuse, because both interferon and ribavirin have many side effects. Common interferon-related side effects include cold-like symptoms, extreme fatigue, nausea, loss of appetite, thyroid disease, hyperglycemia, hair loss, and skin reactions at the injection site. Possible serious interferon-related side effects include psychosis (e.g., suicide), heart disease (e.g., heart attack, hypotension), other internal organ damage, blood disorders (e.g., blood counts falling to dangerous levels), and new or worsening autoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associated side effects include anemia, fatigue, irritability, rash, nasal congestion, sinusitis, and cough. Ribavirin may also cause birth defects, so pregnancy of female and male partners must be avoided during and within 6 months after treatment.

Some patients do not complete treatment due to the severe side effects discussed above; other patients (non-responders) treated but continue to have measurable HCV levels; still other patients (relapsers) are "clear" of the virus during treatment, but repeat some time after completion of the treatment regimen. Accordingly, there remains a need for alternative compounds, compositions and methods of treatment (for use in combination with or in place of interferon agents and/or ribavirin) to alleviate the symptoms of hepatitis c, thereby providing partial or total relief. The present invention provides compounds (including salts thereof), compositions, and methods of treatment that generally address this need.

Disclosure of Invention

The present invention relates to compounds corresponding in structure to formula I-L0:

in formula I-L0:

selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond;

R¹selected from hydrogen, methyl and nitrogen protecting groups;

R²selected from hydrogen, halogen, hydroxy, methyl, cyclopropyl and cyclobutyl;

R³selected from hydrogen, halogen, oxo and methyl;

R⁴selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

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

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group, and

(b) alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, and alkylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:

the amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group, and

(c) carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from alkyl, alkenyl, alkynyl, halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein:

The amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclyl;

R⁵selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halogen;

R⁶selected from the group consisting of fused bicyclic carbocyclic radicals and fused bicyclic heterocyclic radicals, wherein each such substituent is optionally independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KSubstituted with one or more substituents of (a);

each R^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehyde groups, wherein:

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

each R^FIndependently of each otherSelected from alkyl, alkenyl and alkynyl groups, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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, alkynylsulfonyl, alkylsulfonylamino, hydroxyl, and alkoxy, wherein:

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

each R^GIndependently selected from carbocyclyl and heterocyclyl, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, hydroxyl, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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 alkynylsulfonyl;

each R^HIndependently selected from alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkynylsulfonyloxy, wherein:

Each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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 alkynylsulfonyl;

each R^IIndependently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:

(a) alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and

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

carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from halogen, alkyl and oxo;

each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkoxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminminoimino, wherein:

(a) the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl, alkenyl and alkynyl moieties of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, and alkynyloxy, wherein:

alkyl is optionally substituted with one or more hydroxy;

(c) the carbocyclyl and heterocyclyl portions of said substituents being optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, and amino, wherein:

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

each R^KIndependently selected from aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl wherein:

(a) alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl optionally substituted with one or more substituents independently selected from carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, wherein:

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

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

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

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

The invention also relates to methods of using the compounds, salts, compositions and/or kits of the invention, e.g., to inhibit replication of RNA viruses, including HCV, to treat diseases treatable by inhibition of HCV ribonucleic acid (RNA) polymerase, including hepatitis c.

The invention also relates to the use of one or more compounds and/or salts of the invention for the preparation of a medicament. The medicament optionally may contain one or more additional therapeutic agents. In some embodiments, the medicament can be used to treat hepatitis c.

Further advantages of the present invention will be clear to the person skilled in the art from the present patent application.

Drawings

FIG. 1 shows a schematic PXRD pattern of an ethanol solvate of compound IB-L0-2.3.

FIG. 2 shows a schematic TGA profile of an ethanol solvate of compound IB-L0-2.3.

FIG. 3 shows a schematic PXRD pattern of the acetonitrile solvate of compound IB-L0-2.3.

FIG. 4 shows a schematic PXRD pattern of the ethyl acetate solvate of compound IB-L0-2.3.

FIG. 5 shows a schematic PXRD pattern of a 2-propanol solvate of compound IB-L0-2.3.

FIG. 6 shows a schematic PXRD pattern of a methanol solvate of compound IB-L0-2.3.

FIG. 7 shows a schematic PXRD pattern of 1-propanol solvate of compound IB-L0-2.3.

FIG. 8 shows a schematic PXRD pattern for solvent-free crystalline compound IB-L0-2.3.

FIG. 9 shows a schematic PXRD pattern of a hydrate of compound IB-L0-2.3.

FIG. 10 shows a schematic PXRD pattern of mode A monosodium salt of compound IB-L0-2.3.

FIG. 11 shows a schematic TGA profile of mode A monosodium salt of compound IB-L0-2.3.

FIG. 12 shows a schematic PXRD pattern of mode B monosodium salt of compound IB-L0-2.3.

FIG. 13 shows a schematic TGA profile of mode B monosodium salt of compound IB-L0-2.3.

FIG. 14 shows a schematic PXRD pattern of mode C monosodium salt of compound IB-L0-2.3.

FIG. 15 shows a schematic PXRD pattern of the disodium salt of compound IB-L0-2.3.

FIG. 16 shows a schematic TGA profile of the disodium salt of compound IB-L0-2.3.

FIG. 17 shows a schematic PXRD pattern of the monopotassium salt of compound IB-L0-2.3.

FIG. 18 shows a schematic TGA profile of the monopotassium salt of compound IB-L0-2.3.

FIG. 19 shows a schematic PXRD pattern of mode A mono-choline salt of compound IB-L0-2.3.

FIG. 20 shows a schematic TGA profile of mode A monocholinergic salt of compound IB-L0-2.3.

FIG. 21 shows a schematic PXRD pattern of mode B monocholinergic salt of compound IB-L0-2.3.

FIG. 22 shows a schematic TGA profile of mode B monocholinergic salt of compound IB-L0-2.3.

FIG. 23 shows a schematic PXRD pattern of the di-choline salt of compound IB-L0-2.3.

Detailed Description

The following detailed description is merely intended to enable one skilled in the art to understand the invention, its principles, and its practical application to enable one skilled in the art to make and use the invention in various forms, and to thereby make the invention best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. Thus, the present invention is not limited to the embodiments described in the present patent application, and various modifications are possible.

A. Definition of

The term "alkyl" (alone or in combination with other terms) refers to a straight or branched chain saturated hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and still 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, isopentyl, and hexyl. In this definition, the applicant provides illustrative examples throughout the detailed description. These illustrative examples are not provided to be construed as the only choices available to one skilled in the art.

The term "alkenyl" (alone or in combination with other terms) refers to a straight 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 vinyl (ethenyl), 2-propenyl, 3-propenyl, 1, 4-pentadienyl, 1, 4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "alkynyl" (alone or in combination with other terms) refers to a straight or branched chain hydrocarbyl substituent 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 a substituent include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl and 3-butynyl.

The term "carbocyclyl" (alone or in combination with other terms) refers to a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or fully unsaturated (i.e., "aryl") hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bonded together to form a ring of the cyclic substituent). The carbocyclyl group may be monocyclic and typically contains 3 to 6 ring atoms. Examples of such monocyclic carbocyclic groups include cyclopropyl (cyclopropane), cyclobutyl (cyclobutane), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexane), cyclohexenyl, cyclohexadienyl and phenyl. Carbocyclyl may alternatively be 2 or 3 rings fused together, such as naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, indanyl (indanyl), anthryl, phenanthryl, and decahydronaphthyl.

The term "cycloalkyl" (alone or in combination with other terms) refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing from 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups may alternatively be 2 or 3 carbocyclic rings fused together, such as decahydronaphthyl.

The term "aryl" (alone or in combination with other terms) refers to an aromatic carbocyclic group containing from 6 to 14 carbon ring atoms. Examples of aryl groups include phenyl, naphthyl, and indenyl.

In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is prefixed by the "C_x-C_y- "indicates where x is the minimum number of carbon atoms in the substituent and y is the maximum. Thus, for example, "C₁-C₆The "alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. By way of further example, C₃-C₆Cycloalkyl means a saturated hydrocarbon ring containing from 3 to 6 carbon ring atoms.

The term "hydrogen" (alone or in combination with other terms) refers to a hydrogen radical, which can be represented as — H.

The term "hydroxy" (alone or in combination with other terms) means-OH.

The term "nitro" (alone or in combination with other terms) means-NO ₂。

The term "cyano" (alone or in combination with other terms) means-CN, which may also be denoted as-C.ident.N.

The term "keto" (alone or in combination with other terms) refers to an oxygen group, which may be represented as ═ O.

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

The term "amino" (alone or in combination with other terms) means-NH₂。

The term "imino" (alone or in combination with other terms) means NH.

The term "aminoimino" (alone or in combination with other terms) means ═ NNH₂。

The term "halo" or "halo" (alone or in combination with other terms) refers to a fluoro group (which may be represented by-F), a chloro group (which may be represented by-Cl), a bromo group (which may be represented by-Br), or an iodo group (which may be represented by-I).

A substituent is "substitutable" if it includes at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano do not fall within this definition. Further, the sulfur atom in the heterocyclic group containing a sulfur atom may be substituted with one or two oxygen substituents.

If a substituent is described as "substituted," a non-hydrogen radical replaces a hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is one in which at least one non-hydrogen group replaces a hydrogen group on the alkyl substituent. For example, a monofluoroalkyl group is an alkyl group substituted with a fluoro group and a difluoroalkyl group is an alkyl group substituted with two fluoro groups. It will be appreciated that if multiple substituents are present on a substituent, each non-hydrogen group may be the same or different (unless otherwise specified).

If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a substituent is described as being optionally substituted with up to a specified number of non-hydrogen groups, the substituent may be (1) unsubstituted; or (2) substituted with up to a specified number of non-hydrogen groups or with fewer than the maximum number of substitutable positions on the substituent. Thus, for example, if a substituent is described as a heteroaryl group optionally substituted with up to 3 non-hydrogen groups, any heteroaryl group having less than 3 substitutable positions will optionally be substituted with up to as many non-hydrogen groups as the heteroaryl group has substitutable positions. For example, tetrazolyl (having only one substitutable position) is optionally substituted with one non-hydrogen group. By way of further example, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen groups, then a primary amino nitrogen is optionally substituted with up to 2 non-hydrogen groups, while a secondary amino nitrogen is optionally substituted with only 1 non-hydrogen group.

The terms "substituent" and "group" are used interchangeably in this patent application.

The prefix "halo" means that the substituent to which the prefix is attached is substituted with one or more independently selected halogen groups. For example, haloalkyl refers to an alkyl substituent wherein at least one hydrogen group is replaced with a halogen group. Examples of the haloalkyl group include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1, 1, 1-trifluoroethyl. It will be appreciated that if a substituent is substituted with multiple halo groups, these halo groups may be the same or different (unless otherwise specified).

The prefix "perhalogenated" means that each hydrogen group on the substituent to which the prefix is attached is replaced with an independently selected halogen group, i.e., each hydrogen group on the substituent is replaced with a halogen group. If all halogen groups are the same, the prefix generally identifies the halogen group. Thus, for example, the term "perfluoro" means that each hydrogen group on the substituent to which the prefix is attached is substituted with a fluoro group. For example, the term "perfluoroalkyl" refers to an alkyl substituent in which a fluorine group is substituted for each hydrogen group.

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

The term "aminocarbonyl" (alone or in combination with other terms) means-C (O) -NH₂。

The term "oxy" (alone or in combination with other terms) refers to an ether substituent which may be represented as-O-.

The term "alkoxy" (alone or in combination with other terms) refers to an alkyl ether substituent, i.e., -O-alkyl. Examples of such substituents include methoxy (-O-CH)₃) Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "alkylcarbonyl" (alone or in combination with other terms) refers to-c (o) -alkyl.

The term "aminoalkylcarbonyl" (alone or in combination with another term (s)) means-C (O) -alkyl-NH ₂。

The term "alkoxycarbonyl" (alone or in combination with other terms) refers to-C (O) -O-alkyl.

The term "carbocyclylcarbonyl" (alone or in combination with other terms) refers to-c (o) -carbocyclyl.

Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term (s)) means-c (o) -heterocyclyl.

The term "carbocyclylalkylcarbonyl" (alone or in combination with other terms) refers to-c (o) -alkyl-carbocyclyl.

Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with other terms) refers to-c (o) -alkyl-heterocyclyl.

The term "carbocyclic oxycarbonyl" (alone or in combination with other terms) refers to-C (O) -O-carbocyclyl.

The term "carbocyclylalkoxycarbonyl" (alone or in combination with other terms) refers to-c (O) -O-alkyl-carbocyclyl.

The term "thio" or "thia" (alone or in combination with other terms) refers to a thiaether substituent, i.e., an ether substituent in which a divalent sulfur atom replaces an ether oxygen atom. Such a substituent may be represented by-S-. For example, "alkyl-sulfanyl-alkyl" refers to alkyl-S-alkyl (alkyl-sulfanyl-alkyl).

The term "thiol" or "sulfhydryl" (alone or in combination with other terms) refers to a sulfhydryl substituent which may be represented as-SH.

The term "(thiocarbonyl)" (alone or in combination with another term (s)) refers to a carbonyl group in which the oxygen atom is replaced with sulfur. Such substituents may be represented by-C (S) -.

The term "sulfonyl" (alone or in combination with other terms) means-S (O)₂-。

The term "aminosulfonyl" (alone or in combination with other terms) means-S (O)₂-NH₂。

The term "sulfinyl" or "sulfoxyl" (alone or in combination with another term (s)) means-S (O) -.

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

The heterocyclyl group can be monocyclic, 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 monocyclic heterocyclic groups include furyl, dihydrofuryl, tetrahydrofuryl, thiophenyl (thiofuryl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, oxadiazolyl (including 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl (furazanyl) or 1, 3, 4-oxadiazolyl), oxadiazolyl (including 1, 2, 3, 4-oxadiazolyl or 1, 2, 3, 5-triazolyl), Oxadiazolyl (including 1, 2, 3-dioxazolyl, 1, 2, 4-dioxazolyl, 1, 3, 2-dioxazolyl or 1, 3, 4-dioxazolyl), thiazolyl, oxathiolanyl (oxathiolyl), oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridyl (azinyl), piperidyl, diazinyl (including pyridazinyl (1, 2-diazinyl), pyrimidinyl (1, 3-diazinyl) or pyrazinyl (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)), (a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Oxazinyl (including 1, 2, 3-oxathiazinyl, 1, 2, 4-oxathiazinyl, 1, 2, 5-oxathiazinyl, or 1, 2, 6-oxathiazinyl)), oxadiazinyl (including 1, 2, 3-oxadiazinyl, 1, 2, 4-oxadiazinyl, 1, 4, 2-oxadiazinyl, or 1, 3, 5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

The heterocyclic group may optionally be a 2 or 3 ring fused together, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridyl (including pyrido [3, 4-b ] -pyridyl, pyrido [3, 2-b ] -pyridyl or pyrido [4, 3-b ] -pyridyl) and pteridinyl. Other examples of fused ring heterocyclic groups include benzo-fused ring heterocyclic groups such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indolenyl (pseudoindolinyl), isoindolyl (benzopyrazolyl), benzoxazinyl (including quinolyl (1-benzoxazinyl) or isoquinolyl (2-benzoxazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1, 2-benzodioxazinyl) or quinazolinyl (1, 3-benzodioxazinyl)), benzopyranyl (including chromanyl or isobenzodihydropyranyl), benzoxazinyl (including 1, 3, 2-benzoxazinyl, 1, 4, 2-benzoxazinyl, 2, 3, 1-benzoxazinyl or 3, 1, 4-benzoxazinyl) and benzisoxazinyl (including 1, 2-benzisoxazinyl or 1, 4-benzisoxazinyl).

The term "2-fused ring" heterocyclyl (alone or in combination with other terms) refers to a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings. Examples of the 2-fused heterocyclic group include indolizinyl, quinolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, indolenyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, anthracyl, benzodioxolyl, benzodioxanyl, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, and tetrahydroisoquinolinyl.

The term "heteroaryl" (alone or in combination with other terms) refers to an aromatic heterocyclic group containing 5 to 14 ring atoms. Heteroaryl groups can be monocyclic or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents, such as pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl and 1, 3, 5-, 1, 2, 4-or 1, 2, 3-triazinyl; 5-membered ring substituents such as imidazolyl, furyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5 membered fused ring substituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthracenyl; and 6/6 membered fused rings, such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.

The prefix attached to the multicomponent substituent applies only to the first component. For example, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl groups. Thus, C₁-C₆C of alkylcycloalkyl₁-C₆The prefix indicates that the alkyl component of the alkylcycloalkyl contains 1 to 6 carbon atoms; c₁-C₆The prefix is not used to describe the cycloalkyl component. By way of further example, the prefix "halo" on a haloalkoxyalkyl group simply means that the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halo groups. If halogen substitution occurs alternatively or additionally on the alkyl component, the substituent should be described as "halogen-substituted alkoxyalkyl" instead of "haloalkoxyalkyl", and finally, if halogen substitution occurs only on the alkyl component On the component(s), the substituent(s) should be described as "alkoxy haloalkyl".

If a substituent is described as being "independently selected from" a group, then each substituent is selected independently of the other. Thus, each substituent may be the same as or different from each other.

When a substituent is described by a phrase, the rightmost component of the substituent is a component having a free valence state.

When a substituent is described by a formula, the dash on the left side of the formula refers to the substituent moiety having a free valence state.

When describing the linking portion of two other portions of the illustrated chemical structure by chemical formula, the leftmost dash of a substituent refers to the portion of the substituent bonded to the left portion of the illustrated structure. On the other hand, the rightmost dash indicates the substituent moiety bonded to the right portion of the structure shown. For example, if the chemical structure shown is X-L-Y and L is described as-C (O) -N (H) -, the formula is X-C (O) -N (H) -Y.

When the word "comprise" or its equivalent is used in this patent application (including the claims), it is the applicant's meaning that unless the context requires otherwise, these words are to be interpreted in an open-ended sense, rather than in a closed-ended sense, and in this patent application (including the claims) these words are to be so interpreted.

The ChemDraw software was used in this patent application to generate compound names.

The term "amorphous" with respect to a compound refers to a solid state in which the molecules of the compound are not ordered and do not form an identifiable crystal lattice or unit cell. The amorphous compound does not give any characteristic crystal peaks when subjected to X-ray powder diffraction.

The term "crystalline form" with respect to a compound refers to a solid state in which the molecules of the compound are arranged to form an identifiable crystal lattice (i) including identifiable unit cells and (ii) producing diffraction pattern peaks upon exposure to X-ray radiation.

Unless otherwise indicated, the term "purity" refers to the chemical purity of a compound according to conventional HPLC analysis.

The term "phase purity" refers to the solid phase purity of a compound relative to a particular crystalline or amorphous compound as measured by X-ray powder diffraction analysis.

The term "phase pure" refers to purity relative to other solid state forms of a compound, and does not necessarily refer to high chemical purity relative to other compounds.

The term "PXRD" refers to X-ray powder diffraction.

The term "TGA" refers to thermogravimetric analysis.

The term "DSC" refers to differential scanning calorimetry.

B. Compound (I)

The present invention relates in part to compounds corresponding in structure to phenyl-uracil derivatives of formula I:

Among these compounds, the compounds of the present invention,selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond.

In some embodiments of the present invention, the substrate is,is a carbon-carbon single bond. In these embodiments, the compound of formula I corresponds in structure to the following formula (i.e., formula IA):

in other embodiments of the present invention, the substrate may be,is a carbon-carbon double bond. In these embodiments, the compound of formula I corresponds in structure to the following formula (i.e., formula IB):

B1. substituent R¹

R¹Selected from hydrogen, methyl and nitrogen protecting groups.

In some embodiments, R¹Is hydrogen.

In some embodiments, R¹Is methyl.

In some embodiments, R¹Selected from hydrogen and methyl.

In some embodiments, R¹Is a nitrogen protecting group. In these embodiments, the compounds are useful as intermediates for preparing compounds of formula I. Suitable nitrogen protecting groups for preparing compounds of formula I are known to those skilled in the art.

B2. Substituent R²

R²Selected from the group consisting of hydrogen, halogen, hydroxy, methyl, cyclopropyl and cyclobutyl.

In some embodiments, R²Is hydrogen.

In some embodiments, R²Is a halogen. In some such embodiments, R²Selected from fluorine and chlorine. In other such embodiments, R²Is fluorine. In other such embodiments, R ²Is chlorine. In yet other such embodiments, the first and second electrodes are,R²is bromine. In other such embodiments, R²Is iodine.

In some embodiments, R²Is a hydroxyl group.

In some embodiments, R²Is methyl.

In some embodiments, R²Is cyclopropyl.

In some embodiments, R²Is a cyclobutyl group.

In some embodiments, R²Selected from hydrogen, methyl, hydroxy and halogen. In some such embodiments, R²Selected from hydrogen, methyl, hydroxy, fluoro and chloro. In other such embodiments, R²Selected from hydrogen, methyl, hydroxy and fluoro. In other such embodiments, R²Selected from hydrogen, methyl, hydroxy and chlorine. In other such embodiments, R²Selected from hydrogen, methyl, hydroxy and bromine. In other such embodiments, R²Selected from hydrogen, methyl, hydroxy and iodine.

In some embodiments, R²Selected from hydrogen, methyl and halogen. In some such embodiments, R²Selected from hydrogen, methyl, fluorine and chlorine. In other such embodiments, R²Selected from hydrogen, methyl and fluorine. In other such embodiments, R²Selected from hydrogen, methyl and chlorine. In other such embodiments, R ²Selected from hydrogen, methyl and bromine. In other such embodiments, R²Selected from hydrogen, methyl and iodine.

In some embodiments, R²Selected from hydrogen and halogen. In some such embodiments, R²Selected from hydrogen, fluorine and chlorine. In other such embodiments, R²Selected from hydrogen and fluorine. In other such embodiments, R²Selected from hydrogen and chlorine. In other such embodiments, R²Selected from hydrogen and bromine. In addition toIn some such embodiments, R²Selected from hydrogen and iodine.

B3. Substituent R³

R³Selected from hydrogen, halogen, oxo and methyl. In some such embodiments, R³Selected from hydrogen, fluoro, oxo and methyl. In other such embodiments, R³Selected from hydrogen, chlorine, oxo and methyl. In other such embodiments, R³Selected from hydrogen, bromo, oxo and methyl. In other such embodiments, R³Selected from hydrogen, iodine, oxo and methyl.

In some embodiments, R³Selected from hydrogen, halogen and oxo. In some such embodiments, R³Selected from hydrogen, fluorine and oxo. In other such embodiments, R³Selected from hydrogen, chlorine and oxo. In other such embodiments, R ³Selected from hydrogen, bromine and oxo. In other such embodiments, R³Selected from hydrogen, iodine and oxo.

In some embodiments, R³Selected from hydrogen and methyl.

In some embodiments, R³Is hydrogen.

In some embodiments, R³Is methyl.

In some embodiments, R³Is oxo.

In some embodiments, R³Is a halogen. In some such embodiments, R³Is fluorine. In other such embodiments, R³Is chlorine. In other such embodiments, R³Is bromine. In other such embodiments, R³Is iodine.

B4. Substituent R⁴

R⁴Selected from halogen, alkyl, alkenyl, alkynyl, nitroA group, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

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

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group,

(b) alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, and alkylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:

The amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group, and

(c) carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from alkyl, alkenyl, alkynyl, halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein:

the amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

Amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

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

the amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from halogen, alkyl, alkenyl, alkynyl, nitro, cyano,Azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from alkyl, alkenyl, alkynyl, halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein:

the amino group is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) Two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

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

(1) One or two substituents independently selected from alkyl, alkenyl and alkynyl, or,

(2) two substituents which together with the amino nitrogen form a monocyclic heterocyclyl; and

(b) alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of halogen, oxo, nitro, cyano, azido, hydroxy, amino, alkoxy, carbocyclyl and heterocyclyl, wherein amino is optionally substituted with:

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or,

(2) two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(1) One or two substituents independently selected from alkyl, alkenyl and alkynyl, or,

(2) two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:

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

(1) one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or,

(2) two substituents which together with the amino nitrogen form a monocyclic heterocyclic group.

In some embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C ₁-C₄-alkylsulfonyl, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

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

(b)C₁-C₄alkyl radical, C₂-C₄-alkenyl and C₂-C₄-alkynyl is optionally substituted with one or more substituents independently selected from halo, oxo, hydroxy, alkoxy and trimethylsilyl, and

(c)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with up to three substituents independently selected from alkyl, alkenyl, alkynyl, halogen and ammonia, wherein:

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

In some embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

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

(b)C₁-C₄alkyl radical, C₂-C₄-alkenyl and C₂-C₄-alkynyl is optionally substituted with one or more substituents independently selected from halo, oxo, hydroxy, alkoxy and trimethylsilyl, and

(c)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with up to three substituents independently selected from alkyl, alkenyl, alkynyl, halogen and ammonia, wherein:

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

In some embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally substituted with up to three substituents independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo and alkylsulfonylamino.

In some embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally substituted with one or two substituents independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with a substituent selected from alkyl, halo and alkylsulfonylamino.

In some embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally up to three times independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl Is substituted by a substituent, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo and alkylsulfonylamino.

In some embodiments, R⁴Selected from halogen, tert-butyl, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

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

In some embodiments, R⁴Selected from tert-butyl, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

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

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, trimethylsilylalkynyl, alkylcarbon radical, carbocyclyl, alkylheterocyclyl, heterocyclyl, halocarbocyclyl, alkylsulfonylamino and alkylsulfonyl.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkoxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl.

In some embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Selected from halogen, C₁-C₄Alkyl radical, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R ⁴Selected from halogen, C₁-C₄-alkyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Is selected from C₁-C₄Alkyl radical, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R⁴Is selected from C₁-C₄-alkyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Selected from halogen, tert-butyl, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Selected from halogen, tert-butyl, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R⁴Selected from the group consisting of halogen, t-butyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Selected from tert-butyl, C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Selected from tert-butyl, C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R⁴Selected from the group consisting of tert-butyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R⁴Is selected from C₃-C₆Carbocyclyl and 5-6 membered heterocyclyl. In some such embodiments, R⁴Is selected from C₆Carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R ⁴Selected from phenyl and 5-6 membered heteroaryl.

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

Suitable heterocyclic groups for the above embodiments include, for example, furyl, thienyl and pyridyl.

In some embodiments, R⁴Selected from the group consisting of halogen, alkyl and alkoxy.

In some embodiments, R⁴Is an alkyl group.

In some embodiments, R⁴Is a tert-butyl group.

B5. Substituent R⁵

R⁵Selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halogen.

In some embodiments, R⁵Selected from hydrogen, hydroxy, alkoxy and halogen. In some such embodiments, R⁵Selected from hydrogen, hydroxy, alkoxy and fluoro. In other such embodiments, R⁵Selected from hydrogen, hydroxy, alkoxy and fluoro. In other such embodiments, R⁵Selected from hydrogen, hydroxy, alkoxy and chloro. In other such embodiments, R⁵Selected from hydrogen, hydroxy, alkoxy and bromo. In other such embodiments, R⁵Selected from hydrogen, hydroxyl, alkoxy and iodine.

In some embodiments, R ⁵Selected from hydrogen, hydroxy, methoxy and halogen. In some such embodiments, R⁵Selected from hydrogen, hydroxy, methoxy and fluoro. In other such embodiments, R⁵Selected from hydrogen, hydroxy, methoxy and chloro. In other such embodiments, R⁵Selected from hydrogen, hydroxy, methoxy and bromo. In other such embodiments, R⁵Selected from hydrogen, hydroxy, methoxy and iodo.

In some embodiments, R⁵Selected from hydrogen, hydroxy and alkoxy. In some such embodiments, R⁵Selected from hydrogen, hydroxy, methoxy and ethoxy.

In some embodiments, R⁵Is hydrogen.

In some embodiments, R⁵Is a hydroxyl group.

In some embodiments, R⁵Is an alkoxy group.

In some embodiments, R⁵Is methoxy.

In some embodiments, R⁵Is an ethoxy group.

B6. Substituent L

L is a bond, and the compound of formula I corresponds in structure to formula I-L0:

in some such embodiments, the compound corresponds in structure to the following formula (i.e., formulas IA-L0):

in other such embodiments, the compound corresponds in structure to the following formula (i.e., formula IB-L0):

B7. substituent R⁶

In some embodiments, R ⁶Selected from the group consisting of fused bicyclic carbocyclic radicals and fused bicyclic heterocyclic radicals, wherein each such substituent is optionally independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or more substituents of (a).

In some such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are not substituted.

In other such embodiments, the fused bicyclic carbocyclic group and fused bicyclic heterocyclic group are selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s). In some such embodiments, the fused bicyclic carbocyclic group and fused bicyclic heterocyclic group are selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with the substituent(s). In other such embodiments, the fused bicyclic carbocyclic group and fused bicyclic heterocyclic group are selected from R^E、R^FAnd R^JIs substituted with the substituent(s). In other such embodiments, the fused bicyclic carbocyclic group and fused bicyclic heterocyclic group are selected from R^FAnd R^JIs substituted with the substituent(s). In other such embodiments, R is used for fused bicyclic carbocyclic and fused bicyclic heterocyclic groups^JAnd (4) substitution.

In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with two substituents. In some such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R ^E、R^F、R^I、R^JAnd R^KIs substituted with two substituents. In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^FAnd R^JIs substituted with two substituents. In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^FAnd R^JIs substituted with two substituents.

In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KSubstituted with the three substituents of (1). In some such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^F、R^I、R^JAnd R^KSubstituted with the three substituents of (1). In other such embodiments, fusionThe bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^FAnd R^JSubstituted with the three substituents of (1). In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^FAnd R^JSubstituted with the three substituents of (1).

In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one, two or three substituents. In some such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R ^E、R^F、R^I、R^JAnd R^KIs substituted with one, two or three substituents. In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^E、R^FAnd R^JIs substituted with one, two or three substituents. In other such embodiments, the fused bicyclic carbocyclic group and the fused bicyclic heterocyclic group are independently selected from R^FAnd R^JIs substituted with one, two or three substituents.

In some embodiments, R⁶Is optionally independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KA fused bicyclic carbocyclic group substituted with one or more substituents of (a). In some such embodiments, the fused bicyclic carbocyclic group is not substituted. In other such embodiments, the fused bicyclic carbocyclic group is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s). In other such embodiments, the fused bicyclic carbocyclic group is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd two substituents of RK. In other such embodiments, the fused bicyclic carbocyclic group is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KSubstituted with the three substituents of (1). In other such embodiments, the fused bicyclic carbocyclic group is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

In some embodiments, R6 is optionally independently selected from R ^E、R^F、R^G、R^H、R^I、R^JAnd R^KA fused bicyclic heterocyclic group substituted with one or more substituents of (1). In some such embodiments, the fused bicyclic heterocyclic group is not substituted. In other such embodiments, the fused bicyclic heterocyclic group is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s). In other such embodiments, the fused bicyclic heterocyclyl is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with two substituents. In other such embodiments, the fused bicyclic heterocyclyl is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KSubstituted with the three substituents of (1). In other such embodiments, the fused bicyclic heterocyclyl is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

In some of the above embodiments, the optionally substituted fused bicyclic carbocyclic group is selected from naphthyl, dihydronaphthyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl, decahydronaphthyl, indenyl, indanyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl, and hexahydropentalenyl. In some such embodiments, the optionally substituted fused bicyclic carbocyclic group is selected from naphthyl and indanyl. In some such embodiments, the optionally substituted fused bicyclic carbocyclic group is naphthyl. In other such embodiments, the optionally substituted fused bicyclic carbocyclic group is a indanyl. In other such embodiments, the optionally substituted fused bicyclic carbocyclic group is indenyl.

In some of the above embodiments, the optionally substituted fused bicyclic heterocyclic group is selected from

X¹、X²And X³Independently selected from N and c (h);

X⁴selected from N (H), O and S;

X⁵、X⁶and X⁷Independently selected from N and c (h);

X⁸selected from N (H), O and S;

X⁹selected from N (H), O and S;

X¹⁰、X¹¹、X¹²and X¹³Independently selected from N and c (h);

X¹⁴selected from N (H), O and S;

X¹⁵、X¹⁶、X¹⁷and X¹⁸Independently selected from N and c (h);

X¹⁹、X²⁰and X²¹One or more of (a) is N, the remainder are c (h);

X²²、X²³、X²⁴and X²⁵One or more of (a) is N, the remainder are c (h);

X²⁶、X²⁷and X²⁸One or more of (a) is N, the remainder are c (h);

X²⁹、X³⁰，X³¹and X³²One or more of (a) is N, the remainder are c (h);

X³³、X³⁴and X³⁵One or more of (a) is N, the remainder are c (h);

X³⁶、X³⁷、X³⁸and X³⁹One or more of (a) is N, the remainder are c (h);

X⁴⁰、X⁴¹and X⁴²Independently selected from N and c (h);

X⁴³、X⁴⁴and X⁴⁵One is selected from N (H), O and S, the other two are C (H)₂；

X⁴⁶And X⁴⁷One selected from N (H), O and S, the other being C (H)₂；

X⁴⁸、X⁴⁹、X⁵⁰And X⁵¹Independently selected from N and c (h);

X⁵²、X⁵³and X⁵⁴Independently selected from N and c (h);

X⁵⁵selected from N (H), O and S;

X⁵⁶、X⁵⁷and X⁵⁸Independently selected from N and c (h);

X⁵⁹selected from N (H), O and S;

X⁶⁰selected from N (H), O and S;

X⁶¹、X⁶²、X⁶³and X⁶⁴Independently selected from N and c (h);

X⁶⁵selected from N (H), O and S;

X⁶⁶、X⁶⁷、X⁶⁸and X⁶⁹Independently selected from N and c (h);

X⁷⁰、X⁷¹And X⁷²One or more of (a) is N, the remainder are c (h);

X⁷³、X⁷⁴、X⁷⁵and X⁷⁶One or more of (a) is N, the remainder are c (h); and

X⁷⁷and X⁷⁸One of N (H) and the other of C (H)₂。

In some of the above embodiments, the optionally substituted fused bicyclic heterocyclic group is selected from

In some of the above embodiments, the optionally substituted fused bicyclic heterocyclic group is selected from:

in some of the above embodiments, X¹、X²And X³Is C (H).

In some of the above embodiments, X⁵、X⁶And X⁷Is C (H).

In some of the above embodiments, X¹⁰、X¹¹、X¹²And X¹³Is C (H).

In some of the above embodiments, X¹⁵、X¹⁶、X¹⁷And X¹⁸Is C (H).

In some of the above embodiments, X¹⁹、X²⁰And X²¹One is N.

In some of the above embodiments, X²²、X²³、X²⁴And X²⁵One is N.

In some of the above embodiments, X²⁶、X²⁷And X²⁸One is N, X²⁹、X³⁰、X³¹And X³²One is N.

In some of the above embodiments, X⁴⁰、X⁴¹And X⁴²Is C (H).

In some of the above embodiments, X⁴⁸、X⁴⁹，X⁵⁰And X⁵¹Is C (H).

In some of the above embodiments, X⁵²、X⁵³And X⁵⁴Is C (H).

In some of the above embodiments, X⁵⁶、X⁵⁷And X⁵⁸Is C (H).

In some of the above embodiments, X⁶¹、X⁶²，X⁶³And X⁶⁴Is C (H).

In some of the above embodiments, X ⁶⁶、X⁶⁷、X⁶⁸And X⁶⁹Is C (H).

In some of the above embodiments, X⁷⁰、X⁷¹And X⁷²One or more of (a) is N, and the remainder are C (H).

In some of the above embodiments, X⁷³、X⁷⁴、X⁷⁵And X⁷⁶One or more of (a) is N, and the remainder are C (H).

B8. Substituent R^E

Each R^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehyde groups, wherein the amino group is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.

In some embodiments, each R is^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, amino, imino, and aldehyde groups, wherein the amino group is optionally substituted with one or two independently selected alkyl groups.

In some embodiments, each R is^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino.

In some embodiments, each R is^EIndependently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino.

In some embodiments, each R is^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, and azido. In some such embodiments, each R is ^EIs a halogen. In other such embodiments, each R is^EIs a nitro group. In other such embodiments, each R is^EIs a hydroxyl group. In other such embodiments, each R is^EIs oxo. In other such embodiments, each R is^EIs a carboxyl group. In other such embodiments, each R is^EIs cyano. In other such embodiments, each R is^EIs an amino group. In other such embodiments, each R is^EIs an imino group. In other such embodiments, each R is^EIs an azide group.

In some embodiments, each R is^EIndependently selected from the group consisting of halogen, nitro, hydroxy, oxo, carboxy, cyano, amino, and imino.

B9. Substituent R^F

Each R^FIndependently selected from alkyl, alkenyl and alkynyl groups, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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, alkynylsulfonyl, alkylsulfonylamino, hydroxyl, and alkoxy,

wherein:

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

In some embodiments, each RF is independently selected from alkyl, alkenyl, and alkynyl groups, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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, alkynylsulfonyl and alkylsulfonylamino,

Wherein:

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

In some of the above embodiments, each R is independently selected from the group consisting of R, and R^FIndependently selected from alkyl, alkynyl and alkynyl groups, wherein the substituents are not substituted.

In some embodiments, each R is^FIndependently selected from alkyl, alkenyl and alkynyl groups, wherein:

each of said substituents being optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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

wherein:

the amino moiety of the alkylsulfonylamino group is optionally substituted with alkyl.

In some embodiments, each R is^FIs an independently selected alkyl group optionally substituted with a substituent selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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

the amino moiety of the alkylsulfonylamino group is optionally substituted with alkyl.

In some embodiments, each R is^FIs an independently selected alkyl group optionally substituted with a substituent selected from the group consisting of carboxy, halogen, amino, imino, and aminosulfonyl, wherein:

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

In some embodiments, each R is^FIs an independently selected alkyl optionally substituted with an amino group, wherein the amino group is optionally substituted with an alkylsulfonyl group.

In some embodiments, each R is^FIs an independently selected alkyl substituted with an amino group, wherein the amino group is substituted with an alkylsulfonyl group. In some such embodiments, each R is^FIs a methylsulfonylaminomethyl group.

In some embodiments, each R is^FIndependently selected from alkyl, alkenyl and alkynyl groups, wherein:

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

In some embodiments, each R is^FIs an independently selected alkyl group substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.

B10. Substituent R^G

Each R^GIndependently selected from carbocyclyl and heterocyclyl, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, hydroxyl, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, 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, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.

In some of the above embodiments, each R is independently selected from the group consisting of R, and R^GIndependently selected from carbocyclyl and heterocyclyl, wherein said substituents are not substituted.

In some embodiments, each R is^GIndependently selected from carbocyclyl and heterocyclyl, wherein:

each of said substituents being optionally substituted with one or two substituents independently selected from alkyl, carboxy, hydroxy, halogen, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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

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

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

B11. Substituent R^H

Each R^HIndependently selected from alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkynylsulfonyloxy, wherein:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, 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, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.

In some of the above embodiments, each R is independently selected from the group consisting of R, and R^HIndependently selected from alkoxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkynylsulfonyloxy, wherein said substituents are not substituted.

In some embodiments, each R is^HIndependently selected from alkoxy and alkylsulfonyloxy, wherein:

each of said substituents being optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

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

In some embodiments, each R is^HIndependently selected from alkoxy and alkylsulfonyloxy, wherein:

each of said substituents being optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, cyano and aminocarbonyl, wherein:

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

In some embodiments, each R is^HIndependently selected from alkoxy and alkylsulfonyloxy, wherein:

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

In some embodiments, each R is^HIs an independently selected alkoxy group.

In some embodiments, each R is^HIs an independently selected alkylsulfonyloxy group.

B12. Substituent R^I

Each R^IIndependently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:

(a) alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and

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

carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from halogen, alkyl and oxo.

In some embodiments, each R is^IIndependently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein the substituents are not substituted.

In some embodiments, each R is^IIndependently selected from the group consisting of alkylcarbonyl, aminocarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:

(a) the alkylcarbonyl group is optionally substituted with a substituent selected from the group consisting of carboxyl, hydroxyl, halogen, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy and aminocarbonyl, and

(b) the aminocarbonyl group is optionally substituted with a substituent selected from the group consisting of alkyl, alkoxyalkyl, alkylsulfonyl and alkylsulfonylamino.

In some embodiments, each R is^IIndependently selected from alkylcarbonyl and aminocarbonyl, wherein:

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

In some embodiments, each R is^IIndependently selected from alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein:

(a) alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and

(b) the aminocarbonyl group 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 R is independently selected from the group consisting of R, and R^IIndependently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein the substituents are not substituted.

In some embodiments, each R is^IIndependently selected from alkylcarbonyl and aminocarbonyl, wherein:

(a) the alkylcarbonyl group is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and

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

In some embodiments, each R is^IIndependently selected from alkylcarbonyl and aminocarbonyl, wherein:

(a) alkylcarbonyl is optionally substituted with one or two substituents independently selected from carboxy, hydroxy, halogen, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, cyano and aminocarbonyl, and

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

In some embodiments, each R is^IIndependently selected from alkylcarbonyl and aminocarbonyl, wherein:

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

In some embodiments, each R is^IIs an independently selected alkylcarbonyl group.

In some embodiments, each R is^IIs an independently selected aminocarbonyl group.

B13. Substituent R^J

Each R^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkoxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino and alkynylsulfonylaminoimino, wherein:

(a) the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, oxo, and amino, and

(2) The amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl, alkenyl and alkynyl moieties of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, and alkynyloxy, wherein:

alkyl is optionally substituted with one or more hydroxy groups;

(c) the carbocyclyl and heterocyclyl portions of said substituents being optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, and amino, wherein:

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

In some embodiments, each R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino and alkynylsulfonylaminoimino, wherein:

(a) The amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl, alkenyl and alkynyl moieties of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, and alkynyloxy, wherein:

Alkyl is optionally substituted with one or more hydroxy groups;

(c) the carbocyclyl and heterocyclyl portions of said substituents being optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, carboxyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, azido, and amino, wherein:

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

in some of the above embodiments, each R is independently selected from the group consisting of R, and R^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino and alkynylsulfonylaminoimino, wherein said substituents are not substituted.

In some embodimentsIn each R^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino and alkylsulfonylaminoimino, wherein:

(a) The amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl portion of the substituent is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl is optionally substituted with one or more hydroxy groups;

(c) the carbocyclyl and heterocyclyl portions of said substituents being optionally substituted with one or two substituents independently selected from alkyl, carboxy, hydroxy, alkoxy, halogen, nitro, cyano and amino, wherein:

The amino group is optionally substituted with one or two independently selected alkyl groups.

In some embodiments, each R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, wherein:

(a) the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl portion of the substituent is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

The amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl is optionally substituted with one or more hydroxy groups;

(c) the carbocyclyl and heterocyclyl portions of said substituents being optionally substituted with one or two substituents independently selected from alkyl, carboxy, hydroxy, alkoxy, halogen, nitro, cyano and amino, wherein:

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

In some embodiments, each R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino andan alkylsulfonylaminoimino group, wherein:

the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) The amino moiety 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 R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, wherein: the alkyl portion of alkylsulfonylamino and alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, wherein:

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, alkoxy, halo, nitro, cyano, and amino.

In some embodiments, each R is^JIndependently selected from the group consisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino, wherein:

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, alkoxy, halo, nitro, cyano, and amino.

In some embodiments, each R is^JIndependently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:

(a) the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) The alkyl, alkenyl and alkynyl moieties of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIs an independently selected alkylsulfonylamino group wherein:

(a) the amino moiety of the alkylsulfonylamino is optionally substituted with substituents independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from 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, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIs an independently selected alkylsulfonylamino group wherein:

the amino moiety of the alkylsulfonylamino is optionally substituted with substituents independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety 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 R is^JIs an independently selected alkylsulfonylamino group wherein:

the amino moiety of the alkylsulfonylamino group is optionally substituted with substituents independently selected from carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl.

In some embodiments, each R is^JIs an independently selected alkylsulfonylamino group 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, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIs an independently selected alkylsulfonylamino group wherein:

the alkyl portion of the alkylsulfonylamino group is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano.

In some embodiments, each R is^JIs an independently selected alkylsulfonylamino group. In some such embodiments, each R is^JIs a methylsulfonylamino group.

In some embodiments, each R is^JIs an independently selected alkylsulfonylaminoimino group wherein:

(a) the amino moiety of the alkylsulfonylaminoimino is optionally substituted with substituents independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from 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, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

The amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIs an independently selected alkylsulfonylaminoimino group wherein:

the amino moiety of the alkylsulfonylaminoimino is optionally substituted with substituents independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety 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 R is^JIs an independently selected alkylsulfonylaminoimino group wherein:

the amino moiety of the alkylsulfonylaminoimino is optionally substituted with substituents independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl.

In some embodiments, each R is^JIs an independently selected alkylsulfonylaminoimino group wherein:

the alkyl portion of the alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl, and cyano, wherein:

the amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl groups are optionally substituted with one or more hydroxyl groups.

In some embodiments, each R is^JIs independentlyA selected alkylsulfonylaminoimino group wherein:

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

In some embodiments, each R is^JIs an independently selected alkylsulfonylaminoimino group. In some such embodiments, each R is^JIs a methylsulfonylaminoimino group.

In some embodiments, each R is ^JIndependently selected from alkylcarbonylamino and alkoxycarbonylamino, wherein:

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

B14. Substituent R^K

Each R^KIndependently selected from aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl wherein:

(a) alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl optionally substituted with one or more substituents independently selected from carboxy, hydroxy, halogen, amino, nitro, azido, oxo, aminosulfonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, wherein:

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

(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 R is independently selected from the group consisting of R, and R^KIndependently selected from aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl, wherein said substituents are not substituted.

In some embodiments, each R is^KIndependently selected from aminosulfonyl and alkylsulfonyl, wherein:

(a) alkylsulfonyl is optionally substituted with one or two substituents independently selected from carboxy, hydroxy, halogen, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl; and

(b) the aminosulfonyl is optionally substituted with one or two independently selected alkyl groups. In some embodiments, each R is^KIndependently selected from aminosulfonyl and alkylsulfonyl.

C. Embodiments of Compounds of formula I

The substituents R are discussed above¹、R²、R³、R⁴、R⁵、L、R^A、R^B、R^C、R^D、 R⁶、R^E、R^F、R^G、R^H、R^I、R^JAnd R^KVarious embodiments of (a). These substituent embodiments may be combined to form various embodiments of the compounds of formula I. All embodiments of the compounds of formula I formed by combining the substituent embodiments described above are within the scope of the present invention, some illustrative embodiments of which are provided below.

In some embodiments, the compound of formula I corresponds in structure to formula I-L0:

selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond;

R¹selected from hydrogen and methyl;

R²selected from hydrogen and halogen;

R³selected from hydrogen and halogen;

R⁴is selected from C₁-C₄Alkyl radical, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally substituted with up to three substituents independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo and alkylsulfonylamino;

R⁵selected from hydrogen, hydroxy, alkoxy and halogen;

R⁶selected from the group consisting of fused bicyclic heterocyclic groups and fused bicyclic carbocyclic groups wherein each substituent is independently selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with one, two or three substituents;

each R^EIndependently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino;

each R^FIs an independently selected alkyl group optionally substituted with a substituent selected from the group consisting of carboxy, halogen, amino, imino, and aminosulfonyl, wherein:

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

Each R^IIndependently selected from alkylcarbonyl and aminocarbonyl, wherein:

aminocarbonyl is optionally substituted with a substituent selected from the group consisting of alkyl, alkoxyalkyl, alkylsulfonyl and alkylsulfonylamino;

each R^JIndependently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:

(a) the amino moiety of the substituent is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:

(1) 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, alkoxy, halogen, nitro, cyano, oxo, and amino, and

(2) the amino moiety of aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from alkyl, alkenyl and alkynyl,

(b) the alkyl, alkenyl and alkynyl moieties of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halogen, oxo, amino, alkoxycarbonyl, alkylcarbonyloxy, hydroxy, alkoxy, carbocyclyl, heterocyclyl and cyano, wherein:

The amino group is optionally substituted with one or two substituents independently selected from alkyl and alkoxy, wherein:

alkyl is optionally substituted with one or more hydroxy groups; and

each R^KIndependently selected from aminosulfonyl and alkylsulfonyl, wherein:

(a) alkylsulfonyl is optionally substituted with one or two substituents independently selected from carboxy, hydroxy, halogen, amino, nitro, oxo, aminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl; and

(b) the aminosulfonyl is optionally substituted with one or two independently selected alkyl groups. In some embodiments, the compound of formula I corresponds in structure to formula I-L0:

selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond;

R¹is hydrogen;

R²selected from hydrogen and halogen;

R³is hydrogen;

R⁴is a tert-butyl group;

R⁵selected from hydrogen, hydroxy, methoxy and halogen;

R⁶is a fused bicyclic carbocyclic group selected from naphthyl, dihydronaphthyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl, decahydronaphthyl, indenyl, indanyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl and hexahydropentalenyl, wherein each substituent is selected from R ^FAnd R^JSubstituted with the substituent(s);

R^Fis an alkylsulfonyl radicalAn aminoalkyl group; and

R^Jis an alkylsulfonylamino group.

Examples of compounds of formula I (and salts thereof) are shown in tables 1-9 below. The following synthetic examples provide teachings for the stepwise synthesis of some of these compounds. The remaining compounds are prepared using general preparative methods, the following specific synthetic examples, and/or the discussion in this application.

TABLE 1

TABLE 2

TABLE 3

Compound (I)	R5	Substituent group
			IB-L0-2.4	-OCH3	＝NN(H)S(O)2CH3
IB-L0-2.7	-H	＝NN(H)S(O)2CH3
			IB-L0-2.9	-OCH3	(S)-C(H)2N(H)S(O)2CH3
IB-L0-2.10	-OCH3	(R) -F and-C (H)2N(H)S(O)2CH3
			IB-L0-2.12	-OCH3	-F and-C (H)2N(H)S(O)2CH3
IB-L0-2.15	-OCH3	(R)-C(H)2N(H)S(O)2CH3
			IB-L0-2.17	-OCH3	-C(H)2N(H)S(O)2CH3
IB-L0-2.20	-OCH3	(S) -F and-C (H)2N(H)S(O)2CH3
			IB-L0-2.22	-OCH3	(S)-C(CH3)2N(H)S(O)2CH3
IB-L0-2.24	-OCH3	＝NN(H)C(O)OCH3
			IB-L0-2.25	-OCH3	-CH3and-C (H)2N(H)S(O)2CH3
IB-L0-2.29	-OCH3	-C(CH3)2N(H)S(O)2CH3
			IB-L0-2.31	-OCH3	-N(H)N(H)S(O)2CH3
IB-L0-2.34	-OCH3	-C(O)N(H)S(O)2CH3
			IB-L0-2.36	-OCH3	-OH
IB-L0-2.37	-OCH3	(R)-C(CH3)2N(H)S(O)2CH3
			IB-L0-2.44	-OCH3	-N(H)S(O)2CH3
IB-L0-2.50	-OCH3	＝O

TABLE 4

TABLE 5

Compound (I)	R5	Substituent group
			IB-L0-2.11	-OCH3	C(H)2N(H)S(O)2CH3
IB-L0-2.21	-OCH3	-C(H)2N(CH3)S(O)2CH3
			IB-L0-2.35	-Cl	-C(H)2N(H)S(O)2CH3

TABLE 6

TABLE 7

Compound (I)	Substituent group
		IB-L0-2.18	-C(H)2N(H)S(O)2CH3
IB-L0-2.42	-CH3

TABLE 8

TABLE 9

D. Isomers

The present invention also relates, in part, to all isomers (i.e., structures and stereoisomers) of the compounds of formula I (and salts thereof). Structural isomers include chain and positional isomers. 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 stereocenters), and diastereomers (i.e., stereoisomers having the same configuration at one or more stereocenters, but different at other stereocenters).

E. Salt (salt)

The invention also relates in part to all salts of the compounds of formula I. Salts of the compounds may be advantageous due to one or more properties of the salt, for example, enhanced drug stability at different temperatures and humidities, or desirable solubility in water or other solvents. If the salt is intended to be administered to a patient (e.g., as opposed to in vitro use), the salt is preferably pharmaceutically acceptable and/or physiologically compatible. The term "pharmaceutically acceptable" is used as an adjective in this patent application to mean that the modified noun is appropriate as a drug or as part of a drug. Pharmaceutically acceptable salts include those salts commonly used to form alkali metal salts and to form addition salts of the free acids or free bases. In general, for example, these salts can generally be prepared in the conventional manner by reacting the appropriate acid or base with the compounds of the invention.

Pharmaceutically acceptable acid addition salts of the compounds of formula I may be prepared with inorganic or organic acids. Examples of generally 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 organic acids. Specific examples of generally suitable organic acid salts include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, methanesulfonate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, pamoate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylsulfamate, alginic acid, beta-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, bisulfate, hydrogen sulfate, salts of organic acids, Butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glucoheptonate, glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmitate, GaoGumate, 2-naphthalenesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, p-toluenesulfonate and undecanoate.

Pharmaceutically acceptable base addition salts of the compounds of formula I include, for example, metal salts and organic salts. Preferred metal salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiologically compatible metal salts. These salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from amines such as trimethylol methylamine, diethylamine, N' -dibenzyl ethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups capable of being quaternized with agents, e.g. lower alkyl (C)₁-C₆) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and the like.

In some embodiments, the salt is the sodium salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydro-pyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the monosodium salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the disodium salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydro-pyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the potassium salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydro-pyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the mono potassium salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the choline salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydro-pyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

In some embodiments, the salt is the monocholinergic salt of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

F. Purity of

Any level of purity, including pure and substantially pure, of the compounds of formula I (and salts thereof) is within the scope of the invention. The term "substantially pure" with respect to a compound/salt/isomer means that a formulation/composition containing the compound/salt/isomer contains greater than about 85% by weight of the compound/salt/isomer, preferably greater than about 90% by weight of the compound/salt/isomer, preferably greater than about 95% by weight of the compound/salt/isomer, preferably greater than about 97% by weight of the compound/salt/isomer, preferably greater than about 99% by weight of the compound/salt/isomer.

G. Crystalline forms of some specific compounds and salts of the invention

Crystalline form of n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.3).

The present invention also relates, in part, to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.3), i.e., solvates, hydrates, and solventless crystalline forms as described below.

G1A. IB-L0-2.3 solvate

The present invention also relates in part to ethanol solvates of compounds IB-L0-2.3.

In some embodiments, the X-ray powder diffraction pattern of the ethanol solvate comprises one or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 19.2 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the ethanol solvate comprises three or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 19.2 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 Θ °. In other such embodiments, the ethanol solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 19.2 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the ethanol solvate comprises one or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 19.2 ± 0.2, 19.4 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the ethanol solvate comprises three or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 19.2 ± 0.2, 19.4 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 Θ °. In other embodiments, the ethanol solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 8.3 ± 0.2, 9.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 13.6 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 19.2 ± 0.2, 19.4 ± 0.2, 22.7 ± 0.2, 26.9 ± 0.2, and 29.4 ± 0.22 θ °.

In some embodiments, the ethanol solvate has an X-ray powder diffraction pattern substantially as shown in figure 1. The 2 θ values (and their intensities) of the peaks in fig. 1 are as follows: 8.25(54), 9.67(74), 9.92(63), 10.59(21), 13.64(49), 17.25(40), 17.51(20), 19.19(66), 19.43(100), 22.75(19), 26.92(25) and 29.39 (18).

The present invention also relates in part to acetonitrile solvates of compound IB-L0-2.3.

In some embodiments, the acetonitrile solvate has an X-ray powder diffraction pattern comprising one or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 19.1 ± 0.2, and 19.5 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the acetonitrile solvate comprises three or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 19.1 ± 0.2, and 19.5 ± 0.22 Θ °. In other such embodiments, the acetonitrile solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 19.1 ± 0.2, and 19.5 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the acetonitrile solvate comprises one or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 17.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 22.0 ± 0.2, 22.8 ± 0.2, and 27.2 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the acetonitrile solvate comprises three or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 17.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 22.0 ± 0.2, 22.8 ± 0.2, and 27.2 ± 0.22 Θ °. In other such embodiments, the acetonitrile solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 5.3 ± 0.2, 8.3 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 13.8 ± 0.2, 17.2 ± 0.2, 17.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 22.0 ± 0.2, 22.8 ± 0.2, and 27.2 ± 0.22 Θ °.

In some embodiments, the acetonitrile solvate has an X-ray powder diffraction pattern substantially as shown in figure 3. The 2 θ values (and their intensities) of the peaks in fig. 3 are as follows: 5.27(14), 8.29(33), 9.72(100), 10.53(20), 13.77(67), 17.25(38), 17.69(17), 19.05(63), 19.47(58), 22.05(19), 22.75(16) and 27.17 (21).

The present invention also relates in part to the ethyl acetate solvate of compound IB-L0-2.3.

In some embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising one or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 18.7 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °. In some such embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising three or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 18.7 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °. In other such embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 18.7 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °.

In some embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising one or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.7 ± 0.2, 17.4 ± 0.2, 18.7 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 28.2 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °. In some such embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising three or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.7 ± 0.2, 17.4 ± 0.2, 18.7 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 28.2 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °. In other such embodiments, the ethyl acetate solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.7 ± 0.2, 17.4 ± 0.2, 18.7 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 28.2 ± 0.2, 38.5 ± 0.2, and 44.7 ± 0.22 Θ °.

In some embodiments, the ethyl acetate has an X-ray powder diffraction pattern substantially as shown in figure 4. The 2 θ values (and their intensities) of the peaks in fig. 4 are as follows: 7.94(24), 9.33(26), 9.72(13), 10.58(23), 13.71(19), 17.40(28), 18.72(44), 21.69(8), 22.04(10), 28.23(8), 38.45(100) and 44.66 (95).

The present invention also relates in part to 2-propanol solvates of compound IB-L0-2.3.

In some embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern comprising one or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, and 22.5 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the 2-propanol solvate comprises three or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, and 22.5 ± 0.22 Θ °. In other such embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, and 22.5 ± 0.22 Θ °.

In some embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern comprising one or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2, and 28.0 ± 0.22 Θ °. In some such embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern comprising three or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2, and 28.0 ± 0.22 Θ °. In other such embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 8.2 + -0.2, 9.3 + -0.2, 10.1 + -0.2, 16.3 + -0.2, 18.1 + -0.2, 18.6 + -0.2, 19.4 + -0.2, 21.6 + -0.2, 22.5 + -0.2, 23.8 + -0.2, 26.0 + -0.2, and 28.0 + -0.22 θ °.

In some embodiments, the 2-propanol solvate has an X-ray powder diffraction pattern substantially as shown in figure 5. The 2 θ values (and intensities) of the peaks in fig. 5 are as follows: 8.18(32), 9.26(100), 10.12(81), 16.28(93), 18.11(30), 18.59(63), 19.40(67), 21.57(60), 22.51(31), 23.82(29), 25.94(24) and 28.05 (29).

The present invention also relates in part to the methanol solvate of compound IB-L0-2.3.

In some embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises one or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, and 19.6 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises three or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, and 19.6 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises five or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, and 19.6 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises one or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.6 ± 0.2, and 27.1 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises three or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.6 ± 0.2, and 27.1 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the methanol solvate comprises five or more peaks selected from 8.4 ± 0.2, 9.7 ± 0.2, 10.1 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.6 ± 0.2, and 27.1 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the methanol solvate is substantially as shown in figure 6. The 2 θ values (and their intensities) of the peaks in fig. 6 are as follows: 8.36(48), 9.74(65), 10.05(74), 13.55(24), 13.79(69), 17.40(32), 19.30(80), 19.58(100) and 27.08 (24).

The present invention also relates in part to 1-propanol solvates of compounds IB-L0-2.3.

In some embodiments, the X-ray powder diffraction pattern of the 1-propanol solvate comprises one or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 19.3 ± 0.2, 21.6 ± 0.2, and 22.8 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the 1-propanol solvate comprises three or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 19.3 ± 0.2, 21.6 ± 0.2, and 22.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the 1-propanol solvate comprises five or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 19.3 ± 0.2, 21.6 ± 0.2, and 22.8 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the 1-propanol solvate comprises one or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 10.5 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 18.6 ± 0.2, 19.3 ± 0.2, 21.0 ± 0.2, 21.6 ± 0.2, and 22.8 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the 1-propanol solvate comprises three or more peaks selected from 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 10.5 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 18.6 ± 0.2, 19.3 ± 0.2, 21.0 ± 0.2, 21.6 ± 0.2, and 22.8 ± 0.22 Θ °. In other such embodiments, the 1-propanol solvate has an X-ray powder diffraction pattern comprising five or more peaks selected from 8.2 + -0.2, 9.3 + -0.2, 10.1 + -0.2, 10.5 + -0.2, 15.7 + -0.2, 16.2 + -0.2, 18.4 + -0.2, 18.6 + -0.2, 19.3 + -0.2, 21.0 + -0.2, 21.6 + -0.2, and 22.8 + -0.22 θ °.

In some embodiments, the 1-propanol solvate has an X-ray powder diffraction pattern substantially as shown in figure 7. The 2 θ values (and intensities) of the peaks in fig. 7 are as follows: 8.15(27), 9.26(87), 10.08(84), 10.47(62), 15.73(40), 16.24(100), 18.37(41), 18.59(49), 19.33(50), 20.97(28), 21.65(71) and 22.81 (44).

The present invention also relates in part to a process for preparing the above solvates by suspending compound IB-L0-2.3 in the corresponding solvent.

G1B. solvent-free IB-L0-2.3

The present invention also relates, in part, to solvent-free crystalline forms of compound IB-L0-2.3.

In some embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 includes one or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 16.2 + -0.2, and 18.3 + -0.22 θ deg.. In some such embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises three or more peaks selected from 6.2 ± 0.2, 7.9 ± 0.2, 9.9 ± 0.2, 16.2 ± 0.2, and 18.3 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises five or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 16.2 + -0.2, and 18.3 + -0.22 θ °.

In some embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises one or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 10.1 + -0.2, 14.9 + -0.2, 16.2 + -0.2, 18.3 + -0.2, 19.8 + -0.2, and 26.5 + -0.22 theta deg.. In some such embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises three or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 10.1 + -0.2, 14.9 + -0.2, 16.2 + -0.2, 18.3 + -0.2, 19.8 + -0.2, and 26.5 + -0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises five or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 10.1 + -0.2, 14.9 + -0.2, 16.2 + -0.2, 18.3 + -0.2, 19.8 + -0.2, and 26.5 + -0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 comprises eight or more peaks selected from 6.2 + -0.2, 7.9 + -0.2, 9.9 + -0.2, 10.1 + -0.2, 14.9 + -0.2, 16.2 + -0.2, 18.3 + -0.2, 19.8 + -0.2, and 26.5 + -0.22 θ °.

In some embodiments, the X-ray powder diffraction pattern of solvent-free compound IB-L0-2.3 is substantially as shown in FIG. 8. The 2 θ values (and their intensities) of the peaks in fig. 8 are as follows: 6.20(36), 7.85(66), 9.89(61), 10.12(75), 14.87(27), 16.19(89), 18.32(100), 19.82(77) and 26.53 (34).

The present invention also relates, in part, to a process for preparing a solvent-free crystalline form of compound IB-L0-2.3 by desolvating one of the aforementioned IB-L0-2.3 solvates. The solvate can be desolvated by heating the solvate solid at-125 ℃ for about 10 min.

G1C.IB-L0-2.3 hydrate

The present invention also relates, in part, to hydrates of compound IB-L0-2.3.

In some embodiments, the X-ray powder diffraction pattern of the hydrate comprises one or more peaks selected from 6.4 ± 0.2, 12.9 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the hydrate comprises three or more peaks selected from 6.4 ± 0.2, 12.9 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the hydrate comprises one or more peaks selected from 6.4 ± 0.2, 12.9 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 24.4 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the hydrate comprises three or more peaks selected from 6.4 ± 0.2, 12.9 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 24.4 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the hydrate comprises five or more peaks selected from 6.4 ± 0.2, 12.9 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 24.4 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the hydrate comprises one or more peaks selected from 6.4 ± 0.2, 12.7 ± 0.2, 12.9 ± 0.2, 14.1 ± 0.2, 15.7 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, 21.2 ± 0.2, 24.4 ± 0.2, and 25.0 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the hydrate comprises three or more peaks selected from 6.4 ± 0.2, 12.7 ± 0.2, 12.9 ± 0.2, 14.1 ± 0.2, 15.7 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, 21.2 ± 0.2, 24.4 ± 0.2, and 25.0 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the hydrate comprises five or more peaks selected from 6.4 ± 0.2, 12.7 ± 0.2, 12.9 ± 0.2, 14.1 ± 0.2, 15.7 ± 0.2, 17.2 ± 0.2, 17.5 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, 21.2 ± 0.2, 24.4 ± 0.2, and 25.0 ± 0.22 Θ °.

In some embodiments, the hydrate has an X-ray powder diffraction pattern substantially as shown in figure 9. The 2 θ values (and their intensities) of the peaks in fig. 9 are as follows: 6.42(60), 12.71(33), 12.89(58), 14.05(17), 15.68(18), 17.22(44), 17.53(100), 17.86(51), 18.87(77), 21.25(17), 24.35(28) and 24.95 (20).

The present invention also relates in part to a process for preparing a hydrate by suspending the above solvent-free crystalline compound in water. The hydrate was prepared by suspending 300mg of the solvent-free crystalline compound in 2ml of water at 45 ℃ for 4 days.

Crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt

The present invention also relates in part to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, i.e., the following mode a, mode B, and mode C crystalline forms.

The present invention is directed, in part, to the crystalline monosodium salt of mode a.

In some embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises one or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, and 23.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises three or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, and 23.9 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises five or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, and 23.9 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises one or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, and 23.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises three or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, and 23.9 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises five or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, and 23.9 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises one or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 16.0 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 23.9 ± 0.2, and 28.3 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises three or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 16.0 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 23.9 ± 0.2, and 28.3 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode a monosodium salt comprises five or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 16.0 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 23.9 ± 0.2, and 28.3 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode a monosodium salt comprises eight or more peaks selected from 4.6 ± 0.2, 10.4 ± 0.2, 12.0 ± 0.2, 15.6 ± 0.2, 16.0 ± 0.2, 18.6 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 23.9 ± 0.2, and 28.3 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the mode a monosodium salt is substantially as shown in figure 10. The 2 θ values (and their intensities) of the peaks in fig. 10 are as follows: 4.64(62), 10.41(38), 12.04(38), 15.62(44), 15.99(44), 18.63(49), 22.77(60), 23.29(40), 23.93(100) and 28.31 (56).

The present invention also relates in part to a process for preparing the monosodium salt of mode a. The monosodium salt of mode A was prepared by adding 1M aqueous NaOH (0.548ml) to compound IB-L0-2.3(225.72mg), seeding the resulting suspension with crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt (prepared as described below) and equilibrating the resulting suspension at ambient conditions. On the next day, the form a monosodium salt was formed by a solution mediated process. The stoichiometric amount of salt was assumed to be 1: 1 based on the crystallization process. The present invention also relates in part to the crystalline monosodium salt of mode B.

In some embodiments, the X-ray powder diffraction pattern of mode B monosodium salt comprises one or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises five or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises one or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises five or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises eight or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises one or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises two or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises two or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, and 31.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, and 31.8 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 19.2 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt comprises three or more peaks selected from 5.4 ± 0.2, 10.8 ± 0.2, 16.3 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, and 16.3 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 16.3 ± 0.2, and 22.1 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 16.3 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 19.2 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, and 23.7 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, and 31.8 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, and 31.8 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B monosodium salt includes peaks at 5.4 ± 0.2, 10.8 ± 0.2, 14.4 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2, 22.1 ± 0.2, 23.7 ± 0.2, 28.8 ± 0.2, 29.1 ± 0.2, and 31.8 ± 0.22 θ °.

In some embodiments, the mode B monosodium salt has an X-ray powder diffraction pattern substantially as shown in figure 12. The 2 θ values (and their intensities) of the peaks in fig. 12 are as follows: 5.36(100), 10.75(42), 14.43(20), 16.34(60), 17.00(25), 18.83(18), 19.24(18), 19.66(12), 21.64(29), 22.12(41), 23.73(32), 28.83(9), 29.10(9), and 31.78 (10).

The present invention also relates in part to a process for preparing the monosodium salt of mode B. Mode B monosodium salt can be prepared by suspending mode A monosodium salt (e.g., -30 mg) in various organic solvents (e.g., -125 μ l acetonitrile, ethanol, 1-propanol, or 2-propanol) at room temperature. Mode B monosodium salt may also be prepared by seeding the solution with mode B monosodium salt. Compound IB-L0-2.3(12.5g) was dissolved in DMSO (37.5ml) at-68 ℃. 1.04g NaOH dissolved in 6.3ml water, 6.3ml 2-propanol and 12.5ml 35.2: 1v/v 2-propanol/water were added. 125mg of mode B seed solution slurried in 12.5ml 35.2: 1v/v 2-propanol/water was inoculated and the crystallized slurry incubated at-68 ℃ for-1.5 h. 175ml of 35.2: 1v/v 2-propanol/water at-68 ℃ was added in-7 hours, and the crystallized slurry was cooled to-0 ℃ in not less than 7 hours. The crystals were isolated by filtration and analyzed by PXRD. The crystals were then dried under vacuum (approximately 3 inches of mercury) at-50 ℃. The dried crystals were analyzed by PXRD and showed no change compared to the sample before drying. The stoichiometric amount of mode B monosodium salt was confirmed by ion chromatography.

The present invention also relates in part to the crystalline monosodium salt of mode C.

In some embodiments, the X-ray powder diffraction pattern of the mode C monosodium salt comprises one or more peaks selected from 5.0 ± 0.2, 12.0 ± 0.2, 17.5 ± 0.2, 18.8 ± 0.2, and 22.7 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode C monosodium salt comprises three or more peaks selected from 5.0 ± 0.2, 12.0 ± 0.2, 17.5 ± 0.2, 18.8 ± 0.2, and 22.7 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the mode C monosodium salt comprises one or more peaks selected from 5.0 ± 0.2, 12.0 ± 0.2, 17.5 ± 0.2, 17.8 ± 0.2, 18.8 ± 0.2, and 22.7 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises three or more peaks selected from 5.0 ± 0.2, 12.0 ± 0.2, 17.5 ± 0.2, 17.8 ± 0.2, 18.8 ± 0.2, and 22.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of mode a monosodium salt comprises five or more peaks selected from 5.0 ± 0.2, 12.0 ± 0.2, 17.5 ± 0.2, 17.8 ± 0.2, 18.8 ± 0.2, and 22.7 ± 0.22 Θ °.

In some embodiments, the mode C monosodium salt has an X-ray powder diffraction pattern substantially as shown in figure 14. The 2 θ values (and their intensities) of the peaks in fig. 14 are as follows: 4.97(100), 12.03(24), 17.55(32), 17.80(77), 18.79(23) and 22.74 (33).

The present invention also relates in part to a process for preparing the monosodium salt of mode C. Mode C monosodium salt is prepared as follows. Mode B monosodium salt (100mg) was dissolved in 400. mu.l DMSO at 70 ℃ and 2ml 12: 1v/v 2-propanol/H₂And (4) in O. Mode B monosodium salt seeds were added to the solution, and the solution was then cooled to ambient temperature within 20 min. Filtration yielded the crystals of the mode C monosodium salt.

Crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt

The present invention also relates, in part, to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt.

In some embodiments, the disodium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, and 23.0 ± 0.22 Θ °. In some such embodiments, the disodium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, and 23.0 ± 0.22 Θ °. In other such embodiments, the disodium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, and 23.0 ± 0.22 Θ °.

In some embodiments, the disodium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, and 23.3 ± 0.22 Θ °. In some such embodiments, the disodium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, and 23.3 ± 0.22 Θ °. In other such embodiments, the disodium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from 4.8 ± 0.2, 9.6 ± 0.2, 10.5 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, and 23.3 ± 0.22 θ °.

In some embodiments, the disodium salt has an X-ray powder diffraction pattern substantially as shown in figure 15. The 2 θ values (and their intensities) of the peaks in fig. 15 are as follows: 4.80(100), 9.59(10), 10.51(13), 12.98(11), 14.56(8), 15.38(12), 16.84(6), 22.68(10), 23.04(6) and 23.33 (4).

The present invention also relates in part to a process for preparing the disodium salt. The disodium salt was prepared by suspending compound IB-L0-2.3(52.83mg) in 1M aqueous NaOH (1.1ml) in a molar ratio of compound: NaOH of 1: 10. The solution was heated to 36 ℃ and the solid completely dissolved to give a clear solution. The solution was allowed to cool naturally to ambient temperature and the salt crystallized within 24 h. Alternatively, the disodium salt was prepared by suspending compound IB-L0-2.3(51mg) in EtOH (1 ml). 1.2ml of 5: 1v/v EtOH/H were added ₂NaOH (2.1 molar equivalents) in O. The reaction mixture was concentrated, and 2ml of acetonitrile was added to induce crystallization. The stoichiometric amount of the solid was determined by ion chromatography.

Crystalline form of n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monopotassium salt.

The present invention also relates, in part, to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide potassium salt.

In some embodiments, the X-ray powder diffraction pattern of the monopotassium salt comprises one or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the monopotassium salt comprises three or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the monopotassium salt includes five or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the monopotassium salt comprises one or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 21.5 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the monopotassium salt comprises three or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 21.5 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the monopotassium salt includes five or more peaks selected from 5.0 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.3 ± 0.2, 16.9 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 21.5 ± 0.2, 23.5 ± 0.2, 24.8 ± 0.2, and 25.7 ± 0.22 Θ °.

In some embodiments, the monopotassium salt has an X-ray powder diffraction pattern substantially as shown in figure 17. The 2 θ values (and intensities) of the peaks in fig. 17 are as follows: 4.97(100), 9.94(7), 11.33(15), 13.28(7), 16.91(5), 18.13(7), 19.14(4), 20.00(4), 21.13(4), 21.45 (4), 23.54(4), 24.84(3) and 25.67 (6).

The present invention also relates in part to a process for preparing the monopotassium salt. The monopotassium salt is prepared in an aqueous medium. 0.366ml of 1M aqueous KOH solution were added to 150.56mg of compound IB-L0-2.3 (molar ratio 1: 1.2). The resulting suspension was equilibrated at ambient conditions. On the next day, the monopotassium salt was formed by a solution-mediated process. Alternatively, the monopotassium salt was prepared by suspending compound IB-L0-2.3(300mg) in 3ml acetonitrile. 1.3mL of H was added₂KOH in O (2.1 molar equivalents). An additional 1ml of H was added₂O to dissolve all solids. Then, 12ml of acetonitrile was added to induce crystallization. The stoichiometric amount of salt was confirmed by ion chromatography.

Crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monocholine salt

The present invention also relates in part to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monocholine salt, i.e., the following form a and form B crystalline forms.

The present invention is directed, in part, to the crystalline mono-choline salt of mode a.

In some embodiments, the mode a mono-choline salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, and 21.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode a mono-choline salt comprises three or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, and 21.9 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode a mono-choline salt comprises five or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, and 21.9 ± 0.22 Θ °.

In some embodiments, the mode a mono-choline salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.0 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, 19.7 ± 0.2, and 21.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode a monocholinergic salt includes three or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.0 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, 19.7 ± 0.2, and 21.9 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode a monocholinergic salt includes five or more peaks selected from 10.9 ± 0.2, 12.1 ± 0.2, 13.0 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 19.5 ± 0.2, 19.7 ± 0.2, and 21.9 ± 0.22 Θ °.

In some embodiments, the mode a mono-choline salt has an X-ray powder diffraction pattern substantially as shown in figure 19. The 2 θ values (and their intensities) of the peaks in fig. 19 are as follows: 10.94(42), 12.06(20), 12.96(26), 13.42(64), 13.64(27), 15.51(18), 16.98(78), 17.81(26), 18.32(100), 19.49(48), 19.70(33) and 21.91 (22).

The present invention also relates in part to a process for preparing the mode a mono-choline salt. The preparation is carried out in a solvent mixture of Tetrahydrofuran (THF) and methanol. Compound IB-L0-2.3(56.79mg) was dissolved in THF at 60 deg.C, and 40.01mg choline hydroxide solution (45 wt% in methanol) was added to make the molar ratio 1: 1.2. Naturally cooling to ambient temperature to form crystals.

The present invention also relates in part to the crystalline mono-choline salt of mode B.

In some embodiments, the mode B mono-choline salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 22.1 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the mode B mono-choline salt comprises three or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 22.1 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B mono-choline salt comprises five or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 22.1 ± 0.22 Θ °.

In some embodiments, the mode B mono-choline salt has an X-ray powder diffraction pattern comprising one or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.3 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.8 ± 0.2, and 22.1 ± 0.22 Θ °. In some such embodiments, the mode B mono-choline salt has an X-ray powder diffraction pattern comprising three or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.3 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.8 ± 0.2, and 22.1 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the mode B mono-choline salt comprises five or more peaks selected from 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.3 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.8 ± 0.2, and 22.1 ± 0.22 Θ °.

In some embodiments, the mode B mono-choline salt has an X-ray powder diffraction pattern substantially as shown in figure 21. The 2 θ values (and their intensities) of the peaks in fig. 21 are as follows: 7.96(41), 9.38(34), 10.96(24), 12.98(76), 13.34(33), 13.72(37), 15.90(100), 17.03(60), 17.42(37), 18.30(31), 18.85(93), 19.82(90), 21.76(38) and 22.06 (46).

The present invention also relates in part to a process for preparing mode B mono-choline salts. Prepared by suspending amorphous choline salt in ethyl acetate for 7 days.

Crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide dihydrochloride salt

The present invention also relates, in part, to crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide choline salt.

In some embodiments, the X-ray powder diffraction pattern of the digylcholine salt includes one or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 21.9 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the digylcholine salt includes three or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 21.9 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the digylcholine salt includes five or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, and 21.9 ± 0.22 Θ °.

In some embodiments, the X-ray powder diffraction pattern of the digylcholine salt includes one or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.9 ± 0.2, and 22.1 ± 0.22 Θ °. In some such embodiments, the X-ray powder diffraction pattern of the digylcholine salt comprises three or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.9 ± 0.2, and 22.1 ± 0.22 Θ °. In other such embodiments, the X-ray powder diffraction pattern of the digylcholine salt includes five or more peaks selected from 8.6 ± 0.2, 11.0 ± 0.2, 12.9 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.9 ± 0.2, and 22.1 ± 0.22 Θ °.

In some embodiments, the digylcholine salt has an X-ray powder diffraction pattern substantially as shown in figure 23. The 2 θ values (and their intensities) of the peaks in fig. 23 are as follows: 8.62(28), 10.98(29), 12.93(50), 15.88(100), 17.03(42), 17.47(29), 18.88(66), 19.82(57), 21.89(42), 2.07 (41).

The present invention also relates in part to a process for preparing the digylcholine salt. Prepared by suspending compound IB-L0-2.3(200mg) in 0.75ml MeOH. Choline hydroxide in MeOH (210ml, 45 wt%, 2.10 molar equivalents) was added. The reaction mixture was concentrated and 4ml acetonitrile and 6ml isopropyl acetate were added. Traces of compound IB-L0-2.3 monopotassium salt seed (described above) were then seeded into the reaction mixture. The reaction mixture begins to crystallize shortly thereafter. By passing through a solution ¹H NMR determines the stoichiometric amount of the salt.

H. Composition comprising a metal oxide and a metal oxide

The invention also relates, in part, to compositions containing one or more compounds and/or salts of the invention, including the crystalline compounds and salts described in section G above. In some embodiments, the composition contains one or more substantially pure crystalline forms (compound/salt/solvate/hydrate) described in section G above. The composition may be a pharmaceutical composition.

In some embodiments, the composition further comprises one or more additional therapeutic agents. The therapeutic agent may, but need not, be an additional HCV inhibitor.

Preferred compositions will generally contain one or more conventional pharmaceutically acceptable carriers, adjuvants and/or vehicles (collectively "excipients"), depending on the method of administration. Pharmaceutical formulations are generally discussed, for example, in 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 compound or salt is typically combined with one or more excipients. If administered orally, the compound or salt may be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation, for example, may be provided as a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents, such as sodium citrate, magnesium carbonate or bicarbonate or calcium. In addition, tablets and pills may also have an enteric coating.

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

Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection and infusion. Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting and/or suspending agents. Acceptable carriers and solvents include, for example, water, 1, 3-butanediol, ringer's solution, isotonic sodium chloride solution, less irritating non-volatile oils (e.g., synthetic mono-or diglycerides), fatty acids (e.g., oleic acid), dimethylacetamide, surfactants (e.g., ionic and nonionic detergents), and/or polyethylene glycols.

Formulations for parenteral administration may be prepared, for example, as sterile powders or granules with one or more excipients used in orally administered formulations. The compounds or salts of the present invention are soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. If necessary, the pH can be adjusted with suitable acids, bases or buffers.

Suppositories for rectal administration of the compounds or salts of the invention can be prepared, for example, by mixing the compounds or salts with suitable non-irritating excipients which are solid at ordinary temperatures but liquid at the rectal temperature and therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter, synthetic mono-, di-or triglycerides, fatty acids and/or polyethylene glycols.

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

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

A preferred total daily dose of the compound or salt (administered singly or in divided portions) is generally from about 0.001 to about 100mg/kg, more preferably from about 0.001 to about 30mg/kg, and even more preferably from about 0.01 to about 10mg/kg (i.e., mg compound or salt per kg body weight). Dosage unit compositions may contain such amounts or sub-multiples thereof to constitute the daily dose. In many cases, administration of the compound or salt will be repeated multiple times. Multiple doses/day can generally 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; a route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicology of the particular compound or salt employed; whether a drug delivery system is utilized; and whether the compound or salt is administered as part of a pharmaceutical combination. Thus, the dosage regimen actually employed may vary widely and may therefore be selected from the preferred dosage regimens set forth above.

I. Reagent kit

The invention also relates in part to kits containing 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 use of the kit, for example.

J. Application method

The invention also relates in part to methods of inhibiting replication of an RNA virus. The method comprises exposing the virus to one or more compounds and/or salts of the invention. In some embodiments, the replication of the RNA virus is inhibited in vitro. In other embodiments, replication of the RNA virus is inhibited in vivo. In some embodiments, the RNA virus whose replication is inhibited is a single-stranded positive-sense RNA virus. In some such embodiments, the replication-inhibited RNA virus is a virus derived from the Flaviviridae family. In some such embodiments, the RNA virus whose replication is inhibited is HCV.

The present invention also relates in part to methods of inhibiting HCV RNA polymerase. The method comprises exposing the polymerase to one or more compounds and/or salts of the invention. In some embodiments, HCV RNA polymerase activity is inhibited in vitro. In other embodiments, HCV RNA polymerase activity is inhibited in vivo.

The term "inhibit" refers to a reduction in the level of RNA virus replication/HCV polymerase activity in vitro or in vivo. For example, a compound/salt of the invention inhibits RNA virus replication if the compound/salt reduces the level of RNA virus replication by at least about 10% compared to the level of RNA virus replication prior to virus exposure to the compound/salt. In some embodiments, the compound/salt may 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%.

The invention also relates in part to methods of treating diseases that can be treated by inhibiting HCV RNA polymerase. Accordingly, the invention also relates in part to methods of treating 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, a therapeutically effective amount of a compound and/or salt is administered to an animal. By "treating" is meant that the disease being treated is alleviated, inhibited, eliminated, prevented, risk reduced, and/or onset delayed. Applicants specifically use the term "treatment" to encompass the administration of the compounds and/or salts of the present invention to HCV-negative patients as candidates for organ transplantation. The treatment is particularly suitable for humans, but may also be used for other animals, particularly mammals. "therapeutically effective amount" or "effective amount" refers to an amount that achieves the goal of treating a targeted disorder.

In some embodiments, the methods comprise combination therapy wherein a compound and/or salt of the present invention is co-administered with a second (or even a third, fourth, etc.) compound, e.g., another therapeutic agent for the treatment of hepatitis c (e.g., an interferon or interferon/ribavirin combination, or an HCV inhibitor, e.g., an HCV polymerase inhibitor or an HCV protease inhibitor). The compounds and/or salts of the present invention may also be co-administered with therapeutic agents other than those used to treat hepatitis c (e.g., anti-HIV agents). In these co-administration embodiments, the compound and/or salt of the invention and the second isotherapeutic agent can be administered in a substantially simultaneous manner (e.g., within about 5 minutes), in a sequential manner, or both. It is contemplated that such combination therapy may include multiple administrations of one therapeutic agent between administrations of the other therapy. The time between administration of each agent can range from a few seconds (or less) to several hours or days, and depends, for example, on the properties (e.g., potency, solubility, bioavailability, half-life, and kinetics) of each composition and active ingredient, as well as the condition of the patient. The compound and/or salt of the invention and a second such therapeutic agent may also be administered in one formulation.

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

In some embodiments, the medicament is for inhibiting replication of an RNA virus.

In some embodiments, the medicament is for treating hepatitis c.

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

K. Intermediate compound

The present invention also relates, in part, to intermediates that correspond in structure to formula II and that are useful in the preparation of compounds of formula I (and salts thereof) (although some intermediates may also be useful as HCV inhibitors, as may compounds of formula I, and one skilled in the art can determine the ability of compounds of formula II by using, for example, the following methods):

in formula II:

R¹、R²、R³、R⁴and R⁵As described above for the compounds of formula I; and

X²Is a halogen.

R¹、R²、R³、R⁴And R⁵The above embodiments (and combinations thereof) apply to the compound of formula II. With respect to X²In some embodiments, X²Selected from chlorine, bromine and iodine. In other embodiments, X²Selected from chlorine and bromine. In other embodiments, X²Selected from chlorine and iodine. In other embodiments, X²Selected from iodine and bromine. In other embodiments, X²Is fluorine. In other embodiments, X²Is chlorine. In other embodiments, X²Is bromine. In other embodiments, X²Is iodine.

R¹、R²、R³、R⁴、R⁵And X²The above embodiments of (a) may be combined to form embodiments of the compound of formula II and all embodiments of the compound of formula II so formed are within the scope of the present invention. Some exemplary embodiments of the compounds of formula II (and salts thereof) are shown below.

In some embodiments, the compound of formula II corresponds in structure to formula IIA:

in other embodiments, the compound of formula II corresponds in structure to formula IIB:

in some embodiments of the compounds of formula II:

R¹selected from hydrogen, methyl and nitrogen protecting groups;

R²selected from hydrogen and halogen;

R³selected from hydrogen and halogen;

R⁴is selected from C₁-C₄Alkyl radical, C₃-C₆A carbocyclic group and a 5-6 membered heterocyclic group, wherein ：

(a)C₁-C₄-alkyl is optionally substituted with up to three substituents independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo and alkylsulfonylamino;

R⁵selected from hydrogen, hydroxy, alkoxy and halogen; and

X²selected from chlorine, bromine and iodine.

In some embodiments of the compounds of formula II:

is a carbon-carbon double bond;

R¹is hydrogen;

R²selected from hydrogen and halogen;

R³is hydrogen;

R⁴is a tert-butyl group;

R⁵selected from hydrogen, hydroxy and methoxy; and

X²selected from bromine and iodine.

In some embodiments of the compounds of formula II:

R¹selected from hydrogen and methyl;

R²selected from hydrogen and methyl;

R³selected from hydrogen and methyl;

R⁴is a tert-butyl group;

R⁵selected from the group consisting of hydroxy and methoxy; and

X²selected from chlorine, bromine and iodine.

In some embodiments of the compounds of formula II:

is a carbon-carbon double bond;

R¹is hydrogen;

R²is hydrogen;

R³is hydrogen;

R⁴is a tert-butyl group;

R⁵selected from the group consisting of hydroxy and methoxy; and

X²selected from chlorine, bromine and iodine.

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

The following discussion provides indications for the preparation of intermediate compounds of formula II (and salts thereof).

L. starting compound

The present invention also relates in part to starting compounds that correspond in structure to formula III and that are useful in the preparation of compounds (and salts thereof) of formulae II and I:

in formula III， R¹、R²And R³As described above for the compounds of formula I and II.R¹、R²And R³The above embodiments (and combinations thereof) apply to the compound of formula III.R¹、R²And R³The above embodiments of (a) may be combined to form embodiments of the compound of formula III, and all embodiments of the compound of formula III so formed are within the scope of the present invention. Some exemplary embodiments of the compounds of formula III (and salts thereof) are shown below.

In some embodiments of the compounds of formula III:

R¹selected from hydrogen, methyl and nitrogen protecting groups;

R²selected from hydrogen and halogen; and

R³selected from hydrogen and halogen.

In some embodiments of the compounds of formula III:

is a carbon-carbon double bond;

R¹selected from hydrogen;

R²selected from hydrogen and halogen; and

R³selected from hydrogen.

In some embodiments of the compounds of formula III:

R¹selected from hydrogen and methyl;

R²selected from hydrogen and methyl; and

R³selected from hydrogen and methyl.

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

The present invention also relates in part to starting compounds that correspond in structure to formula IV and that are useful in the preparation of compounds (and salts thereof) of formulae II and I:

In formula IV:

R⁴，R⁵and X²As described above for the compounds of formula I and II; and

X¹is a halogen.

R⁴、R⁵And X²The above embodiments (and combinations thereof) apply to the compound of formula IV. With respect to X¹In some embodiments, X¹Selected from chlorine, bromine and iodine. In other embodiments, X¹Selected from chlorine and bromine. In other embodiments, X¹Selected from chlorine and iodine. In other embodiments, X¹Selected from iodine and bromine. In other embodiments, X¹Is fluorine. In other embodiments, X¹Is chlorine. In other embodiments, X¹Is bromine. In other embodiments, X¹Is iodine. With respect to X¹And X²In some embodiments, X¹And X²The same is true.

R⁴、R⁵、X¹And X²May be combined to form embodiments of the compound of formula IV, and all of the compounds of formula IV so formedEmbodiments are within the scope of the invention. Some exemplary embodiments of the compounds of formula IV (and salts thereof) are shown below.

In some embodiments of the compounds of formula IV:

R⁴is selected from C₁-C₄Alkyl radical, C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally substituted with up to three substituents independently selected from halogen, oxo, hydroxy, alkoxy and trimethylsilyl, and

(b)C₃-C₆-carbocyclyl and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo and alkylsulfonylamino;

R⁵selected from hydrogen, hydroxy and alkoxy;

X¹selected from chlorine, bromine and iodine; and

X²selected from chlorine, bromine and iodine.

In some embodiments of the compounds of formula IV:

R⁴selected from tert-butyl;

R⁵selected from hydrogen, hydroxy and methoxy;

X¹selected from bromine and iodine; and

X²selected from bromine and iodine.

In some embodiments of the compounds of formula IV:

R⁴selected from tert-butyl;

R⁵selected from the group consisting of hydroxy and methoxy;

X¹selected from chlorine, bromine and iodine; and

X²selected from chlorine, bromine and iodine.

In some embodiments of the compounds of formula IV:

R⁴is a tert-butyl group;

R⁵selected from the group consisting of hydroxy and methoxy;

X¹selected from chlorine, bromine and iodine; and

X²selected from chlorine, bromine and iodine.

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

The following discussion provides indications for the preparation of the starting compounds of formula IV (and salts thereof).

L. preparation method

The invention also relates in part to a process for preparing a compound of formula II. The process comprises reacting a compound of formula III with a compound of formula IV in the presence of (I) a copper (I) salt catalyst and (ii) a nitrogen-containing heteroaryl ligand:

In the above scheme, R¹、R²、R³、R⁴、R⁵、X¹And X²As described above.

The applicant has found that said process generally allows the substitution of the N1 hydrogen of uracil derivative compound III, thus obtaining intermediate compound II. X in intermediate Compound II²When it is chlorine, bromine or iodine, orCompound II is suitable for subsequent reaction (e.g., Suzuki coupling with an appropriate boronic acid or boronic ester) to provide the compound of formula I. In other words, X in intermediate Compound II²The above process is also suitable for the preparation of compounds of formula I, when chlorine, bromine or iodine.

In some embodiments, compound III is uracil and compound IV corresponds in structure to a compound selected from the group consisting of compounds IV-I, IV-Br and IV-Cl, with compounds IV-I and IV-Br generally yielding better yields than compounds IV-Cl.

Suitable Cu (I) catalysts include, for example, CuI, CuBr, CuCl, Cu₂O and CH₃C (O) OCu. In some embodiments, the catalyst is selected from CuI and CuBr. In some such embodiments, the catalyst is CuI. In other such embodiments, the catalyst is CuBr.

In some embodiments, the method is performed in the presence of a base. In some such embodiments, the base is an inorganic base. Suitable inorganic bases include, for example, potassium, sodium, and cesium salts (e.g., K) ₂CO₃、K₃PO₄、Cs₂CO₃、Na₂CO₃). In some embodiments, the base is selected from potassium salts and cesium salts. In some such embodiments, the salt is selected from K₃PO₄And Cs2CO₃. In some embodiments, the base comprises a potassium salt. In some such 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 such embodiments, the cesium salt is Cs₂CO₃。

Typically, the process is carried out in the presence of a solvent. Suitable solvents include, for example, dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), and acetonitrile (MeCN). In some embodiments, the solvent is DMSO.

Typically, the process is carried out at a temperature of from about 40 to about 130 ℃.

In some embodiments, the nitrogen-containing heteroaryl ligand comprises 8-hydroxyquinoline. In other embodiments, the ligand comprises 2- (2-pyridyl) -benzimidazole. In other embodiments, the ligand comprises a picolinamide compound corresponding in structure to formula V:

in the formula V, R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷Independently selected from hydrogen, C_1-4-perfluoroalkyl group, C_1-4-alkoxy, C_1-4-haloalkyl, chloro or cyano. In some embodiments, R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷Independently selected from hydrogen, methyl, methoxy, trifluoromethyl, chloro and cyano. In some embodiments, the ligand of formula V comprises N- (4-cyanophenyl) picolinamide. In other embodiments, the ligand of formula V comprises N- (2-cyanophenyl) picolinamide.

In some embodiments, the method comprises (a) preparing a compound of formula IV; and (b) reacting a compound of formula III with a compound of formula IV in the presence of (I) a copper (I) salt catalyst and (ii) a nitrogen-containing heteroaryl ligand, optionally in the presence of an inorganic base.

By, for example, converting 2-tert-butylphenol to 2-tert-butyl-4, 6-diiodophenol (e.g., by reacting it with NaI and NaOCl), and then converting 2-tert-butyl-4, 6-diiodophenol to 1-tert-butyl-3, 5-diiodo-2-methoxybenzene (e.g., by reacting it with CH in the presence of a base (e.g., NaOH)₃I treatment), compounds of formula IV-I may be prepared.

By, for example, converting 2-tert-butylphenol to 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 to 1, 5-dibromo-3-tert-butyl-2-methoxybenzene (for example, by using CH in the presence of KOtBu)₃I treatment), compounds of formula IV-Br can be prepared.

Additional information regarding the preparation of compounds of formula I and II (and salts thereof) is provided in the general discussion and/or specific synthetic examples below. In the following discussion, R unless otherwise indicated ¹、R²、R³、R⁴、R⁵、L、R^A、R^B、R^C、R^D、R⁶、R^E、R^F、R^G、R^H、R^I、R^J、R^K、X¹And X²Have the meaning as described above.

Scheme 1

Compound (1-1) wherein R⁷Is, for example, hydrogen or-CO₂Me and R⁸Is, for example, hydrogen or t-butyl, and can be treated with nitric acid in a solvent such as acetic acid or water at a temperature of from about 0 to about 35 c for a period of from about 1 to about 5 hours to provide compound (1-2). Compound (1-2) can then be reduced using conditions known to those skilled in the art to provide the corresponding aniline (1-3). Typical conditions for reduction include the use of hydrogen at about 1 to about 5 atmospheres in the presence of a catalyst such as palladium or platinum on carbon in a solvent such as tetrahydrofuran, ethyl acetate, ethanol or hexane at or near ambient temperature for about 1 to about 12 hours. Depending on the functional groups present, alternative reduction processes may be more suitable, for example, in the presence of mild acids such as ammonium chloride or dilute hydrochloric acidIron powder is used for about 1 to about 12 hours at reflux temperature in a solvent mixture of, for example, methanol, water and/or tetrahydrofuran. Another set of reducing conditions includes the use of sodium borohydride in a solvent mixture of, for example, water and tetrahydrofuran. Another set of reducing conditions includes the use of stannous (II) chloride in a solvent such as water and methanol or mixtures thereof in the presence of hydrochloric acid.

The compound (1-2) may be modified before reduction. For example, treatment of a mixture of methanol and water at or near ambient temperature with iodine monochloride wherein R is⁷Compound (1-2) which is hydrogen for about 8 to about 24 hours, providing compound (1-4), wherein X¹Is iodine. Alternatively, compound (1-2) may be treated with pyridinium tribromide in a solvent such as acetic acid for about 2 to about 16h at or near ambient temperature to provide compound (1-4), wherein X is¹Is bromine. Modifications may be introduced in the phenol moiety of the compounds (1-4). For example, phenol can be alkylated with an alkyl halide (e.g., methyl iodide), alkyl sulfate (e.g., methyl sulfate), alkenyl halide (e.g., allyl bromide), alkynyl halide (e.g., propargyl bromide) in the presence of a base such as potassium carbonate in acetone, sodium hydride in dimethylformamide, or potassium tert-butoxide in tetrahydrofuran at a temperature of about 0 to about 35 ℃ for about 1 to about 24 hours to provide compound (1-5), wherein R is⁹For example, alkyl, alkenyl or alkynyl. Alternatively, alkylation may be achieved by using a reagent such as (trimethylsilyl) diazomethane in a solvent such as methanol or tert-butyl methyl ether or mixtures thereof for about 8 to about 24 hours in a sealed tube at or near room temperature. Then, the compound (1-5) can be reduced to the compound (1-6) using the above-mentioned iron powder or stannous chloride (II) conditions. An alternative reduction process is hydrogenation at about 1 atmosphere using a catalyst such as 5% platinum on sulfided carbon in a solvent such as methanol. Protection of the resulting aniline compound (1-6) with, for example, tert-butyl carbamate can be achieved by treatment with di-tert-butyl dicarbonate in a solvent such as tetrahydrofuran or dioxane for about 1 to about 8h at a temperature of about 50 to about 65 ℃ to provide compound (1-7).

Modification may also occur in the phenol moiety of the compound (1-2). One skilled in the art can alkylate the phenol compound (1-2) using, for example, the above conditions to obtain the compound (1-8). Compounds (1-8) are converted to compounds (1-9) using, for example, one or more of the suitable reducing conditions described above.

Another modification of the phenol group in the compound (1-2) is sulfonylation to provide a compound (1-8) wherein R is⁹Is alkylsulfonyl, carbocyclylsulfonyl or haloalkylsulfonyl. Such compounds can be prepared by exposing compound (1-2) to a sulfonyl chloride, such as methanesulfonyl chloride, cyclohexanesulfonyl chloride, benzenesulfonyl chloride, or 3-chloropropanesulfonyl chloride, in the presence of a base, such as triethylamine, diisopropylethylamine, or pyridine, in a solvent, such as dichloromethane, at or near ambient temperature for about 1 to about 24 hours. Then, one skilled in the art can convert compound (1-8) to compound (1-9) using suitable reducing conditions.

Scheme 2

Aniline (2-4) can be prepared by using Curtius rearrangement. For this purpose, R in which R is treated with a catalytic amount of dimethylformamide in refluxing thionyl chloride⁴The compound (2-1) other than an amino group is present for about 1 to about 4 hours to provide the acid chloride (2-2). Treatment with thionyl chloride in a solvent such as chloroform or toluene at reflux temperature also affords compound (2-2). Compound (2-2) may be reacted with an aqueous solution of sodium azide in a solvent such as acetone for about 1 to about 8 hours to provide the acyl azide (2-3). Then, compound (2-3) may undergo Curtius rearrangement in a refluxing solvent 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 compound (2-4).

Scheme 3

Compound (3-1) wherein R¹⁰For example hydrogen, bromine, iodine or-CO₂Me can be treated with acrylic acid in a solvent such as toluene at or near ambient temperature and heated to reflux for about 15 to about 48 hours to provide compound (3-2). When acrylic acid is used, the compound (3-3) is produced. Compound (3-2) or (3-3) can be treated with urea in a solvent such as acetic acid at about 100 to about 120 deg.C for about 2 to about 48 hours to provide compound (3-4).

Scheme 4

Compound (4-2) can be prepared from compound (3-1) dissolved in a solvent such as dimethylformamide or dimethylacetamide by adding a benzene solution of (E) -3-methoxyacryloyl isocyanate (prepared according to Santana, L. et al, J.Heterococcus chem.1999, 36, 293-295) and then raising to ambient temperature for about 30min to about 4h under an inert atmosphere at a temperature of about-40 to about-15 ℃. Compound (4-2) is treated with an acid, such as sulfuric acid, in a mixture of water and ethanol at a temperature of about 90 to about 110 c for about 1 to about 8 hours to provide compound (4-3). Alternatively, compound (4-2) may be described in Ueno, y, et al, j.org.chem.70: 7925-7935(2005) to uracil (4-3).

Scheme 5

Wherein R is treated with an electrophilic halide source such as iodine monochloride⁴Phenol (20-1) other than an amino group to provide a dihalogenated compound (20-2), wherein X is¹And X²Independently bromine or iodine. Compound (20-2) is converted to compound (20-3) by reaction of an alkylating agent such as methyl sulfate with a base such as potassium carbonate in refluxing acetone. Alternatively, methyl iodide in the presence of a base such as potassium tert-butoxide in a solvent such as tetrahydrofuran or dimethylformamide also provides compound (20-3). In another alternative, compound (20-2) may be methylated with (trimethylsilyl) diazomethane in a solvent such as tert-butyl methyl ether. Compound (20-3) can be reacted with uracil ligand (20-4), copper (I) iodide, and potassium phosphate in dimethylsulfoxide at about 40 ℃ to about 100 ℃ to provide compound (20-5).

For example, when R in the compound (20-3)⁴Is tert-butyl, X¹Is iodine and X²When iodine or bromine is used, the compound (20-3) may be present in CuI and K₂PO₄With uracil and compound (20-4) in DMSO at about 60 ℃ for about 15 to about 24 hours to provide compound (20-5). Other options for ligands (20-4) for preparation (20-5) are 8-hydroxyquinoline and 2- (2-pyridyl) -benzimidazole.

Scheme 6

Compound (25-1) is brominated by treatment with, for example, pyridinium tribromide, for about 1 to about 8 hours in a solvent such as acetic acid at or near ambient temperature to afford compound (25-2). The amino group of compound (25-2) is removed by exposure to tert-butyl nitrite in a solvent such as dimethylformamide, initially at ambient temperature, and then raised to a temperature of from about 50 to about 65 ℃, to give compound (25-3). At ambient temperature, an additional portion of tert-butyl nitrite was added and then heated until conversion was complete. Compound (25-3) can be reduced to compound (25-4) by, for example, treatment with iron and ammonium chloride.

Scheme 7

The compound (26-1), wherein each Z is independently N or CH, may be converted to a boronic ester for use in a Suzuki reaction. For example, a compound of formula (26-1) may be converted to compound (26-2) by treatment with methanesulfonyl chloride in pyridine at about ambient temperature for about 1 to about 8h, wherein R¹⁴Is hydrogen or methanesulfonyl (when excess methanesulfonyl chloride is used).

Compound (26-2) may be converted to a compound of formula (26-3) by treatment with pinacol-borane in the presence of a catalyst such as tris (dibenzylideneacetone) dipalladium (0), a ligand such as tri-tert-butylphosphine and a base such as triethylamine in a solvent such as tetrahydrofuran, dioxane or toluene at a temperature of from ambient to about 130 ℃.

Optionally in a catalyst such asDichloro [1, 1' -bis (diphenylphosphino) ferrocene]Compound (26-2) may be reacted with bis (pinacolato) diboron in the presence of a palladium (II) dichloromethane adduct or palladium acetate in the presence of a ligand such as 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (XPhos) and a base such as potassium acetate in a solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at a temperature of about 60 to about 130 ℃ to give compound (26-3).

Compound (26-3) can be converted to the protected compound (26-4) by treatment with benzylbutyl chloroformate, initially at about 0 ℃, in a mixture of acetone and water in the presence of saturated aqueous sodium bicarbonate. The temperature may then be raised to ambient and maintained at that temperature for about 12 to about 24 hours. Then, using the above reaction conditions, the compound (26-4) can be converted into the boronic acid pinacol ester (26-5).

Scheme 9

Compound (26-5), wherein each Z is independently N or CH, can be coupled with compound (1-7) under Suzuki reaction conditions to provide compound (27-3). Such conditions include, for example, the use of a palladium catalyst, such as tris (dibenzylideneacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium, or dichloro [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloromethane adduct; a base such as potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran, or a mixture thereof heated at a temperature of about 40 to about 130 ℃.

Compound (27-3) can be converted into compound (27-4) in a three-step process. The first step involves removal of the tert-butoxycarbonyl protecting group by treatment with an acid such as trifluoroacetic acid in a solvent such as hydrochloric acid in dichloromethane or dioxane at room temperature for about 1 to about 24 h. The dihydropyrimidinediones can then be introduced as in scheme 3.

Compound (27-5) can be obtained from compound (27-4) in a two-step process. First, the protecting group is removed from the naphthylamine under reducing conditions. Typically, the hydrogenation (1 atmosphere) is carried out in the presence of a catalyst such as 10% palladium on charcoal in a solvent such as ethyl acetate at or near ambient temperature for about 8 to about 24 hours. Next, the naphthylamine can be sulfonylated by treatment with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent (e.g., dichloromethane) at room temperature for about 20min to about 4 h.

Scheme(s)10

A compound (28-1) wherein each Z is independently N or CH, R¹⁵For example hydrogen, -NHSO₂Me、-N(SO₂Me)₂Or a methoxy group, which can be coupled with compound (1-7) under Suzuki reaction conditions to provide compound (28-2). Such conditions include, for example, the use of palladium catalysts, such as tris (dibenzylideneacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium or dichloro [1, 1' -bis (diphenylphosphino) ferrocene ]A palladium (II) dichloromethane adduct; a base such as potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran, or a mixture thereof heated at a temperature of about 40 to about 130 ℃. The reaction is typically deoxygenated with an inert gas, such as nitrogen, prior to heating. The heating may be carried out in a conventional glassware, sealed tube, or microwave reactor for about 1 to about 24 hours.

Compound (28-2) can be converted into compound (28-3) in a three-step process. The first step involves removal of the tert-butoxycarbonyl protecting group by treatment with an acid such as trifluoroacetic acid in a solvent such as hydrochloric acid in dichloromethane or dioxane at room temperature for about 1 to about 24 h. Uracil can then be introduced as in scheme 4.

Scheme 11

A compound (28-1) wherein each Z is independently N or CH, R¹⁵For example hydrogen, -NHSO₂Me、-N(SO₂Me)₂Or methoxy, which can be coupled with a compound of formula (29-2) under Suzuki reaction conditions, wherein X¹For exampleIs bromine or iodine to provide the compound of formula (28-3). Such conditions include, for example, the use of palladium catalysts such as tris (dibenzylideneacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium, dichloro [1, 1' -bis (diphenylphosphino) ferrocene ]Palladium (II) dichloromethane adduct or bis (diphenylphosphino) ferrocene]Palladium (II) dichloromethane; a base such as potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran, or a mixture thereof heated at a temperature of about 40 to about 130 ℃. The reaction is typically deoxygenated with an inert gas, such as nitrogen, prior to heating. The heating may be carried out in a conventional glassware, sealed tube, or microwave reactor for about 1 to about 24 hours.

Scheme 12

In catalysts such asDichloro [1, 1' -bis (diphenylphosphino) ferrocene]Compound (30-1) wherein X is X in the presence of a palladium (II) dichloromethane adduct or palladium acetate in the presence of a ligand such as 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (XPhos) and a base such as potassium acetate in a solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at a temperature of 60-130 deg.C¹Is bromine or iodine, N is 1 or 2, and Z is CH or N, can be reacted with bis (pinacolato) diboron to give compound (30-2). The reaction is typically deoxygenated with an inert gas, such as nitrogen, prior to heating. The heating can be carried out in a conventional glassware, a sealed tube or a microwave reactor for 1-24 h. Compound (30-3) can be reacted with compound (30-2) using the conditions described in scheme 11 to give compound (30-4).

Treating compound (30-4) with methanesulfonyl hydrazide in a solvent such as tetrahydrofuran, methanol or ethanol or a mixture thereof at ambient temperature to about 100 ℃ for 8-48 h to provide compound (30-5).

Scheme 13

Compound (31-1) may be treated with hexamethylditin or hexabutylditin in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) chloride in a solvent such as toluene or dioxane heated to about 50 to about 130 ℃ to provide compound (31-2). Compound (31-2) may be treated with compound (31-3) in the presence of a catalyst such as tris (dibenzylideneacetone) palladium (0) and a ligand such as tris (2-furyl) phosphine in a solvent such as toluene, dioxane or tetrahydrofuran heated to about 40 to about 130 ℃ to provide compound (31-4).

Scheme 14

The dinitroaniline (34-1) is sulfonylated by treatment with methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at room temperature for about 8 to about 36 hours to provide compound (34-2). Compound (34-2) can be converted to compound (34-3) using iron powder in the presence of a mild acid such as ammonium chloride or dilute hydrochloric acid in a solvent mixture such as methanol, water, and tetrahydrofuran at reflux temperature for about 1 to about 12 hours.

Scheme 15

Compound (35-1) may be reacted with compound (35-2) in the presence of air-exposed charcoal in a solvent such as toluene heated from about 90 to about 110 ℃ for about 24 to about 72 hours, wherein Z¹Is O, S or NH, R¹⁶Is hydrogen, -NHSO₂Me or NO₂To obtain compound (35-3).

Scheme 16

Iron powder is used in the presence of a mild acid such as ammonium chloride or dilute hydrochloric acid in a solvent such as methanol, ethanol, water, and tetrahydrofuran, or mixtures thereof, at a temperature of about 60 to about 90 ℃, for about 30min to about 12h, compound (36-1), wherein Z is²Is O or S, and can be reduced to the compound (36-2). Compound (39-2) may be sulfonylated by treatment with methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at room temperature for about 8 to about 36 hours.

Scheme 17

Compound (37-1) may be sulfonylated to give compound (37-2) by treatment with methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at room temperature for about 8 to about 36 h. Compound (37-2) may be reacted with (4-methoxyphenyl) methanethiol in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide heated to about 90 to about 110 ℃ for about 8 to about 24 hours to provide compound (37-3). Compound (37-3) can be reduced to compound (37-4) using iron powder in the presence of a mild acid such as ammonium chloride or dilute hydrochloric acid in a solvent such as methanol, ethanol, water, and tetrahydrofuran, or mixtures thereof, at a temperature of about 60 to about 90 ℃ for about 30min to about 12 h. Compound (37-4) may be converted to compound (37-5) in the presence of mercury (II) acetate, anisole, and trifluoroacetic acid at about 0 ℃ for about 30 to about 90 minutes, after which hydrogen sulfide is bubbled through the mixture. Compound (37-5) is treated with compound (37-6) in the presence of p-toluenesulfonic acid and triphenylphosphine in a solvent such as toluene heated to reflux for about 2 to about 16h to provide compound (37-7).

Scheme 18

Compound (38-1) wherein X is¹Is bromine or iodine and Z²Is O or S, can be reacted with 2, 5-hexanedione to give the compound of formula (38-2). In catalysts such asDichloro [1, 1' -bis (diphenylphosphino) ferrocene]Compound (38-2) may be reacted with a reactive bis (pinacolato) diboron in the presence of a palladium (II) dichloromethane adduct or palladium acetate in the presence of a ligand such as 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (XPhos) and a base such as potassium acetate in a solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at a temperature of about 60 to about 130 ℃ to give compound (38-3). Compound (38-3) can be reacted with compound (38-4) under Suzuki reaction conditions to give compound (38-5). Such conditions include, for example, the use of a palladium catalyst, such as dihydrodichlorobis (di-tert-butylphosphinato-KP) palladate (2-), tris (dibenzylideneacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium or dichloro [1, 1' -bis (diphenylphosphino) ferrocene]A palladium (II) dichloromethane adduct; bases, e.g. potassium acetate, potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium carbonate, carbon Cesium acid or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran, or a mixture thereof heated at a temperature of about 40 to about 130 ℃.

Compound (38-5) can be treated with hydroxylamine hydrochloride in heated ethanol to remove the pyrrole-protecting group. Then, treatment with methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at or near ambient temperature provides compound (38-6).

Examples

The following examples are illustrative only and do not limit the invention in any way.

Example a. preparation of (E) -N- (3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl) -3-methoxyacrylamide.

Part a. preparation of 2-tert-butyl-4-nitrophenol.

To a vigorously stirred solution of 2-tert-butylphenol (10g, 66.6mmol) in heptane (67ml) was added rapidly dropwise a solution of 70% nitric acid (4.25ml, 66.6mmol) diluted with water (4.25 ml). The resulting dark red/brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration, washed with hexane (300mL), water (200mL), and again with hexane (200mL) to give a cocoa colored powder, dried to constant weight (4.65g, 35.6%).

Part b. preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

To the product of part A (4.5g, 23.05mmol) dissolved in MeOH (120mL) and water (30mL) was added iodine monochloride (1.155mL, 23.05mmol) dropwise over 10 min. The mixture was stirred for 2h, diluted into 1L of water and left overnight. The solid material was collected by filtration, washed with 3X 50mL of water and dried under vacuum overnight to give a brown solid (7.14g, 96%).

Part c. preparation of 1-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

To an ice-cooled solution of the product of part B (5.5g, 17.13mmol) in a 50mL pressurized vessel in MTBE (15mL) was added 2.0M TMS diazomethane (12.85mL, 25.7mmol) followed by dropwise addition of methanol (1.0mL) to allow the bubbles to settle. The vessel was sealed, stirred at room temperature for 16h, cooled and the pressure released. The solution was partitioned between EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil which was used without purification (5.4g, 84%).

Part d. preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

A mixture of the product of part C (5.80g, 17.31mmol), ammonium chloride (1.389g, 26.0mmol) and iron (4.83g, 87mmol) in THF/MeOH/water (200mL total, 2/2/1) was refluxed for 2h, cooled, and filtered through Celite. The filtrate was evaporated and the residue 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 (5.28g, 100% yield).

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

To a solution of the product of part E at-20 deg.C (3.05g, 10mmol) in DMF (50ml) under nitrogen was added rapidly dropwise a 0.4M benzene solution of (E) -3-methoxyacryloyl isocyanate (50.0ml, 20.00mmol, prepared according to the method of Santana et al, J.Heterocyclic chem.36: 293 (1999)). The solution was stirred at-20 ℃ for 15min, warmed to room temperature, held for 45min, and diluted into EtOAc. The EtOAc layer was washed with water 4X 300mL, brine 2X 100mL, and dried (Na)₂SO₄) And concentrated to a brown solid. The residue is in Et₂Trituration in O/hexane afforded a fine powder, which was collected by filtration and dried to give a brown powder (2.46g,57％)。

example b. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H, 3H) -dione.

To a suspension of the product of example A (2.46g, 5.69mmol) in ethanol (50mL) was added 5.5mL of H₂SO₄50mL of an aqueous solution, and the mixture was heated at 110 ℃ for 2.5h to give a clear solution. The solution was cooled and diluted with 50mL of water with stirring to give an off-white solid which was collected by filtration, washed with water and dried (2.06g, 90%).

Example c. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

Part a. preparation of 2-tert-butyl-4, 6-diiodophenol.

A solution of 2-tert-butylphenol (20.0g, 133mmol) in methanol (266mL) was treated with sodium hydroxide pellets (6.39g, 160 mmol). The mixture was stirred until all the sodium hydroxide had dissolved and then cooled to-2 ℃ in an ice salt bath. Sodium iodide (15.0g, 100mmol) was added, and then a 10% sodium hypochlorite solution (45mL, 73.3mmol) was added dropwise at a rate such that the temperature of the solution was raised to not higher than 1.3 ℃. This procedure was repeated (3X) until a total of 60g (400mmol) of sodium iodide was added and sodium hypochlorite solution was added until the solution changed color from pale green-yellow to pale iced tea. This required 16mL of a total of 180mL of sodium hypochlorite solution to be dosed. Cooling at about 2 ℃ was continued and a solution of sodium thiosulfate pentahydrate (20g) in water (100mL) was added dropwise over 20 min. After addition, the solution was acidified to pH 3 by the addition of concentrated hydrochloric acid (about 35mL out of 40mL in the funnel was required). The precipitate was collected by filtration and washed with > 1 l of water. The orange-red solid was drained as far as possible and dried in a vacuum oven at 50 ℃ for 18 h. These procedures afforded the product (49.61g, 93%) as a brown solid.

Part b. preparation of 1-tert-butyl-3, 5-diiodo-2-methoxybenzene.

A solution of the product of part A (20.0g, 49.7mmol) in acetone (140mL) was treated with methyl iodide (3.9mL, 8.83g, 62.2mmol) and 50% (w/w) sodium hydroxide solution (3.02mL, 4.58g, 57.2mmol) and then stirred at ambient temperature for 48 h. The mixture was concentrated in vacuo to a volume of about 50-60mL, then diluted with heptane (80mL) and water (50 mL). The layers were separated and the organic layer was extracted with saturated sodium chloride solution. Drying (Na)₂SO₄) And concentrated in vacuo to afford the product (20.59g, 99%) as a pale yellow oil.

Part c. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

A suspension of the product of part B (12.04g, 28.9mmol), uracil (3.89g, 34.7mmol), N- (2-cyanophenyl) picolinamide (1.29g, 5.79mmol) and tripotassium phosphate (12.9g, 60.8mmol) in DMSO (181mL) was degassed by nitrogen sparging for 1 h. The mixture was then treated with copper (I) iodide (551mg, 2.89mmol) and degassing continued for an additional 10 min. The mixture was then warmed at 60 ℃ for 18 h. The mixture was then poured into water (600mL) and acidified to pH3 by the addition of 4N hydrochloric acid solution. The mixture was diluted with ethyl acetate and the organic layer was extracted with water (3 ×), saturated ammonium chloride solution (1 ×) and saturated sodium chloride solution. The solution was dried, treated with (3-mercaptopropyl) silica gel and then stirred for 2 h. The mixture was filtered and concentrated in vacuo. The resulting solid was triturated with ether-ethyl acetate (> 10: 1), collected by filtration and washed with ether. After drying in a vacuum oven at 50 ℃ for 2h, these procedures afforded the product (2.75g) as a white solid. The mother liquor was concentrated in vacuo to afford an amber solid. The material was chromatographed on a Flash 65 silica gel column, eluting with 20-100% ethyl acetate in hexane. These procedures afforded a nearly white solid, which was triturated with ether-hexane and collected by filtration. After drying in a vacuum oven for 3h, these procedures provided an additional 4.31g of product as a white solid. Total yield: 7.06g (61%).

Example d. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

Part a. preparation of 2-tert-butyl-4, 6-diiodophenol.

2-tert-butylphenol (99.95g, 665.36mmol) was dissolved in 1250mL of methanol, converted to the corresponding phenate salt with 31.96g (799.0mmol, 1.2 equivalents) of sodium hydroxide by stirring the sodium hydroxide pellets at room temperature, and then the reaction mixture was cooled in an ice/salt bath. Sodium iodide (299.34g, 1997.07mmol, 3.0 equiv.) and 8.3% bleach (1265.83g, 1411.39mmol, 2.1 equiv.) were added in four equal portions to the cold reaction solution, with the bleach added while maintaining the reaction mixture at < 0 ℃. 500mL of a 20% (w/w) sodium thiosulfate solution was added over 18-minutes, and the temperature was raised from-0.6 ℃ to 2.5 ℃. The pH of the reaction mixture was adjusted to about 3 by adding 197.5mL of concentrated HCl over 97min and the reaction temperature was increased from 1.2 ℃ to 4.1 ℃. The resulting slurry was filtered and the wet cake washed with 2L of water. The wet cake was placed on a buchner funnel and vacuum overnight (about 15h) to give 289.33g (effective adjusted yield 254.61g) of the title product.

Part b. preparation of 1-tert-butyl-3, 5-diiodo-2-methoxybenzene.

The product of part A (93% assay, 21.6g, 50mmol) was dissolved in 140mL of acetone. Methyl iodide (4.2mL, 67.5mmol, 1.35 equiv.) was added followed by 50% aqueous sodium hydroxide (5.0g, 62.5mmol, 1.25 equiv.). The reaction was stirred overnight and then concentrated to approximately 50-60 mL. 80mL of heptane was added followed by 50mL of water, the layers were shaken and separated, and the aqueous layer was back-extracted with 20mL of heptane. The organic layers were combined and washed twice with 50mL (each time) of 10% aqueous NaCl to provide 91.1 g of a heptane solution, which was analyzed to be 19.1g of the title compound.

Part c. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

Uracil (33.3g, 297mmol, 1.2 equiv.), K₃PO₄(106g, 500mmol, 2.1 equiv.), CuI (4.6g, 24.2mmol, 0.1 equiv.), and N- (2-cyanophenyl) picolinamide (6.4g, 28.7mmol, 0.12 equiv.) were added to the flask and inerted with argon. The 1-tert-butyl-3, 5-diiodo-2-methoxybenzene solvent was converted to MeCN, dissolved in 1L DMSO, sparged with argon and added to the solid. The reaction was heated to 60 ℃ and held for 16 h. After cooling, the reaction was diluted with 2LEtOAc and washed with 2.6L of water (back-extracted with 3X 1L EtOAc). The organic layers were combined, washed with 2X 1L of 0.25M (CuOAc)₂Then 2X 830mL of 15% NH₄Cl, then washed with 800mL brine. The organic layer was then concentrated, 1L heptane was added, and triturated with refluxing 85: 15(v/v) heptane: iPrOAc for 4 h. After cooling, the product was collected by filtration, washed with an additional 330mL of 85: 15v/v heptane: EtOAc and dried to give 66.9g (70% yield) of the product as a white solid.

Example e. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

A solution of 100mL of water and 300mL of THF was sparged with nitrogen and then transferred by catheter and nitrogen pressure to a flask containing 19.9965g (49.96mmol) of the product of example D, 20.8234g (59.97mmol, 1.20 equivalents) of N- (6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl) methanesulfonamide and 21.8711g (103.03mmol, 2.06 equivalents) of potassium phosphate which had been flushed with nitrogen. The resulting solution was again sparged with nitrogen.

THF (100mL) was sparged with nitrogen and then transferred through a conduit and nitrogen pressure to a solution containing 462.8mg (0.51mmol, 0.01 equiv.) of Pd₂dba₃And 735.8mg (2.52mmol, 0.05 eq.) of 1, 3, 5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phospha-damantane in a flask which had been flushed with nitrogen. The resulting solution was again sparged with nitrogen.

The initial THF/water solution was transferred via a catheter and nitrogen pressure to a flask containing a solution of catalyst and ligand in THF. The reaction was raised to 50 ℃ and stirred overnight under positive nitrogen pressure. The next morning, reaction samples were taken. HPLC of the sample showed 0.28 PA% iodouracil starting material, 76.8 PA% product, and 5.2 PA% borate.

The reaction was cooled to room temperature and washed three times with 550mL of aqueous solution of 5.84g L-cysteine and 81.4g sodium chloride, which had been sparged with nitrogen. The THF solution was filtered through a pad of Celite. The pad was rinsed with 100mL THF and mixed with the initial THF solution. The THF solution was concentrated to 136g on a rotary evaporator. To the white slurry was added 405mL of ethyl acetate with thorough stirring. After stirring overnight the slurry was filtered. The wet cake was washed with 2X 50mL of ethyl acetate. The solid, ethyl acetate solvate, was dried in a vacuum oven at 50 ℃. The weight was 25.49 g.

The solid and 8.7g of 3-mercaptopropyl-derivatized silica gel were stirred in 500mL of THF and then filtered through a pad of Celite. The filtrate was concentrated on a rotary evaporator to give 13.08g of a white solid. The solid filtered off over a pad of Celite was extracted with 500mL of THF at 60 ℃. The THF solution was concentrated to 66g and treated with 206mL of ethyl acetate. The precipitated solid was filtered and dried to obtain 9.13g of a product. This solid was mixed with the initial solid to form a slurry in 100mL of 200proof 3A ethanol. Filtration and drying in a vacuum oven at 50 ℃ gave 20.74g of product.

EXAMPLE 1 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (Compound IA-L0-2.9).

Part a. preparation of 6-bromo-2-naphthoic acid.

A solution of methyl 6-bromo-2-naphthoate (7.70g, 29.0mmol) in 2: 1 THF: water (150mL) was treated with lithium hydroxide hydrate (2.44g, 58.1mmol) and stirred at room temperature for 48 h. Concentrate in vacuo, dilute with water, and cool to 0 ℃. Acidification to pH 3 with 4N HCl. The solid was collected by filtration, dissolved in toluene-EtOAc (ca 2L), and washed with brine. With Na₂SO₄Drying, filtering and vacuum concentrating. The brown solid was triturated with ether, collected by filtration and dried in vacuo to give the title compound as a near white solid (5.07g, 70%).

Part b. preparation of 6-bromonaphthalen-2-amine.

A solution of part of the product A (5.07g, 20.19mmol) and triethylamine (4.22mL, 3.07g, 30.3mmol) in dry DMF (155mL) was treated with diphenylphosphoryl azide (6.55mL, 8.34g, 30.3mmol) and then stirred at room temperature for 3 h. The solution was then treated with water (20mL) and then heated at 100 ℃ for 1 h. The solution was cooled, the flask was fitted with a short path distillation head and DMF was removed by high vacuum distillation. The solid residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution. Filter through Celite and wash the filtrate with water (3 ×), then brine. With Na₂SO₄Drying, filtration, and concentration in vacuo afforded the title compound as an off-white solid (4.48g, 100%).

Part c. preparation of benzyl butyl 6-bromonaphthalen-2-ylcarbamate.

The product of fraction B (1.79g, 8.06mmol) at 0 ℃ was treated with dropwise benzylbutyl chloroformate and saturated sodium bicarbonate solutionSolution (18mL) in acetone (40 mL). The mixture was stirred at 0 ℃ for 1h and then gradually warmed to room temperature for 18 h. The mixture was diluted with EtOAc and water and the layers were separated. The organic layer was extracted with water and washed with brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound as a pink solid (1.5g, 52%).

Part d. preparation of benzyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-ylcarbamate.

A resealable Schlenk tube containing a solution of the product of part C (1.42g, 3.99mmol), bis (pinacolato) diboron (1.11g, 4.39mmol) and potassium acetate (1.17g, 11.96mmol) in DMF (28mL) was degassed by three freeze-thaw cycles. The solution was treated with 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (98mg, 0.12mmol) and then degassed by two additional freeze-thaw cycles. The Schlenk tube was then sealed and the mixture was heated at 80 ℃ for 18 h. Cool and dilute with ethyl acetate and water. The mixture was treated with Darco G-60 and then filtered through Celite. The filtrate was extracted with water (4 ×) and saturated sodium chloride solution. With Na₂SO₄Drying, filtration and concentration in vacuo afforded a light brown oil. Purification by column chromatography on silica eluting with EtOAc/hexanes gave the title compound as a colorless oil (910mg, 57%).

Part e. preparation of 2-tert-butyl-4-nitrophenol.

To a vigorously stirred solution of 2-tert-butylphenol (10g, 66.6mmol) in heptane (67ml) was added rapidly dropwise a solution of 70% nitric acid (4.25ml, 66.6mmol) diluted with water (4.25 ml). The resulting dark red/brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration, washed with hexane (300mL), water (200mL), and again with hexane (200mL) to give a cocoa colored powder, dried to constant weight (4.65g, 35.6%).

Part f. preparation of 2-bromo-6-tert-butyl-4-nitrophenol.

A solution of the product of part E (1.0g, 5.12mmol) in glacial acetic acid (10.25mL) was treated with pyridinium tribromide (1.80g, 5.63mmol) in portions, and then stirred at room temperature for 2 h. Additional pyridinium tribromide (3.6g) was added in two portions and after stirring for an additional 3h, the reaction was complete. The mixture was poured into ice water and the mixture was treated with a small amount of sodium sulfite. The resulting solid was filtered and dried in vacuo to give the title compound as a brown solid (1.40g, 100%).

Part g. preparation of 1-bromo-3-tert-butyl-2-methoxy-5-nitrobenzene.

A solution of the product of part F (1.40g, 5.11mmol) in 10: 1 tert-butylmethyl ether-methanol (25.5mL) was treated with a 2.0M solution of trimethylsilyldiazomethane in ether (5.1mL, 10.21mmol) and then stirred at room temperature for 18 h. The mixture was concentrated in vacuo to provide a yellow oil, which was purified by silica gel column chromatography eluting with EtOAc/hexanes to provide the title compound as a yellow oil (1.36g, 92%).

Part h. preparation of tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenyl carbamate.

A solution of the product of part G (960mg, 3.33mmol) in methanol (17mL) was treated with 5% platinum on carbon sulfide (100mg) and then hydrogenated at balloon pressure for 3h, then filtered through Celite and concentrated in vacuo to afford 3-bromo-5-tert-butyl-4-methoxyaniline as a yellow oil (860mg, 3.33mmol, 100%). A solution of this material in THF (17mL) was treated with di-tert-butyl dicarbonate (800mg, 3.66mmol) and then heated at reflux for 2 h. Concentration in vacuo afforded a beige solid, which was purified by silica gel column chromatography eluting with EtOAc/hexanes. The solid was triturated with hexanes, collected by filtration, and dried under vacuum to give the title compound as a near white solid (890mg, 75%).

Preparation of benzyl 6- (3-tert-butyl-5- (tert-butylcarbamoyl) -2-methoxyphenyl) naphthalen-2-ylcarbamate.

Toluene (928. mu.l) and EtOH (928. mu.l) were mixed with the product of part H (133mg, 0.37mmol), the product of part D (299mg, 0.74mmol) and 1M sodium carbonate (371. mu.l, 0.37mmol) and degassed with nitrogen for 20 min. Tetrakis (triphenylphosphine) palladium (0) (8.6mg, 7.4. mu. mol) was added and degassing continued for 5-10 min. Heating at 85-90 deg.C for 18h, cooling, and vacuum concentrating. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound (102mg, 49%).

Part j. preparation of benzyl 6- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-ylcarbamate.

The product of part I (100mg, 0.18mmol) was treated with trifluoroacetic acid (0.5ml, 6.5mmol) for CH at room temperature₂Cl₂(1.0ml) solution for 1 h. And (4) concentrating in vacuum. Dissolved in ethyl acetate and washed with 11% NaHCO₃And washing with brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Dissolved in toluene (1.0ml), Et was added₃N (25. mu.l, 0.18mmol) and acrylic acid (13. mu.l, 0.19mmol), and the mixture was refluxed for 16 h. And (4) concentrating in vacuum. Dissolved in acetic acid (1.0ml, 17.5mmol), added with urea (11.9mg, 0.20mmol) and refluxed for 72 h. Cooling, pouring into ice water, and adding CHCl ₃Extracting for three times, mixing the extracts, and adding Na₂SO₄Drying, filtering and vacuum concentrating. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound (57.5mg, 58%).

Part k. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

The product of fraction J (56mg, 0.10mmol) and EtOAc (1.0mL) were combined and 10% palladium on charcoal (10mg) was added. Stirred in a hydrogen balloon for 16 h. Filter through Celite and concentrate in vacuo. Is dissolved in CH₂Cl₂(1.0ml), Et was added₃N (16. mu.l, 0.115mmol) and methanesulfonyl chloride (8.7. mu.l, 0.112mmol) were stirred at room temperature for 30 min. Concentrate in vacuo and purify by silica gel column chromatography eluting with EtOAc/hexanes to give the title compound (10mg, 20%).¹H NMR(300MHz，DMSO-d₆)δ1.34-1.48(m，9H)2.71(t，J＝6.62Hz，2H)3.08(s，3H)3.21(s，3H)3.82(t，J＝6.62Hz，2H)7.26(s，2H)7.41(dd，J＝8.82，1.84Hz，1H)7.59-7.76(m，2H)7.89-8.04(m，3H)10.03(s，1H)10.34(s，1H)；MS(ESI+)m/z 496(M+H)⁺；(ESI-)m/z 494(M-H)^-。

Example 2a. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.3).

Part a. preparation of N- (6-bromonaphthalen-2-yl) methanesulfonamide.

A solution of the product of example 1, part B (4.48g, 20.17mmol) in pyridine (100mL) was treated with methanesulfonyl chloride (1.97mL, 2.89g, 25.2mmol) dropwise and then stirred at room temperature for 1 h. Diluted with toluene and concentrated twice in vacuo. The residue was extracted with EtOAc, washed with water, 1M citric acid and brine. Treatment with Darco G-60, Na ₂SO₄Dried, filtered through Celite, and concentrated in vacuo. The solid was triturated with ether-hexane, collected by filtration and dried under vacuum to give the title compound as a pale pink solid (3.32g, 55%).

Part b. preparation of N- (6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl) methanesulfonamide.

A mixture of the product of part A (1.00g, 3.33mmol), bis (pinacolato) diboron (1.27g, 5.00mmol), potassium acetate (0.98g, 9.99mmol) and Combiphos Pd6(84mg, 0.17mmol) in toluene (22mL) was heated under reflux for 3 h. Cool and dilute with ethyl acetate and water. The mixture was treated with Darco G-60 and filtered through Celite. The filtrate was washed with water and brine. With Na₂SO₄Drying, filtering and vacuum concentrating. The oil was dissolved in ether and precipitated by addition of hexane. The product was collected by filtration and washed with hexane. The filtrate was evaporated and purified by silica gel column chromatography eluting with EtOAc/hexanes. Passing through the knotCrystallization and chromatography gave the title compound as a white solid (927mg, 80%).

Part c. preparation of tert-butyl 3-tert-butyl-4-methoxy-5- (6- (methylsulfonylamino) naphthalen-2-yl) phenylcarbamate.

The product of example 1, part H (87mg, 0.243mmol), part B (169mg, 0.486mmol), toluene (1.0ml), ethanol (1.0ml) and sodium carbonate (0.243ml, 0.243mmol) were mixed in a sealed tube and degassed with nitrogen for 20 min. Tetrakis (triphenylphosphine) palladium (0) (5.61mg, 4.86. mu. mol) was added and degassing continued for 5-10 min. Heating at 90-95 deg.C for 16 h. Cooled and concentrated in vacuo. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound (92.2mg, 76%).

Part d. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

The product of part C (90mg, 0.180mmol) was treated with trifluoroacetic acid (1.0ml, 12.98mmol) for CH at room temperature₂Cl₂(2.0ml) solution for 1 h. Concentrated in vacuo and the residue dissolved in EtOAc and washed with 10% NaHCO₃And a brine wash. With Na₂SO₄Drying, filtering and vacuum concentrating. Dissolved in DMF (1.4ml), cooled to-25 ℃ and (E) -3-methoxy-acryloyl isocyanate (0.633ml, 0.361mmol) added dropwise while maintaining the temperature below-10 ℃. The temperature is raised to room temperature and stirred for 2 h. Pour into ether and wash with water and brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Addition of H₂SO₄A mixture of (0.1ml, 1.876mmol), water (1.0ml) and EtOH (1.0ml) was stirred at 100 ℃ for 16 h. Cooled and concentrated in vacuo. Poured into water, extracted with EtOAc, and the extracts were combined and washed with brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with MeOH/CHCl₃Elution gave the title compound (53mg, 59%).¹H NMR(300MHz DMSO-d₆)δ1.42(s，9H)3.08(s，3H)3.25(s，3H)5.65(d，J＝7.72Hz，1H)7.34(dd，J＝15.81，2.57Hz，2H)7.42(dd，J＝8.82，1.84Hz，1H)7.65-7.76(m，2H)7.80(d，J＝8.09Hz，1H)7.96(t，J＝8.27Hz，2H)8.02(s，1H)10.04(s，1H)11.41(s，1H)；MS(ESI+)m/z494 (M+H)⁺；(ESI-)m/z 492(M-H)^-。

Example 2b. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.3).

Part a. preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

To the product of example 1, part E (4.5g, 23.05mmol) dissolved in MeOH (120mL) and water (30mL) was added iodine monochloride (1.155mL, 23.05mmol) dropwise over 10 min. The mixture was stirred for 2h, diluted into 1L of water and left overnight. The solid material was collected by filtration, washed with 3X 50mL of water and dried under vacuum overnight to give a brown solid (7.14g, 96%).

Part b. preparation of 1-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

To an ice-cooled solution of the product of part A (5.5g, 17.13mmol) in a 50mL pressurized vessel in MTBE (15mL) was added 2.0M trimethylsilyldiazomethane (12.85mL, 25.7mmol) and methanol (1.0mL) was added dropwise to allow the bubbles to settle. The vessel was sealed, stirred at room temperature for 16h, cooled and the pressure released. The solution was partitioned between EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil which was used without purification (5.4g, 84%).

Part c. preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

A mixture of the product of part B (5.80g, 17.31mmol), ammonium chloride (1.389g, 26.0mmol) and iron (4.83g, 87mmol) in THF/MeOH/water (200mL total, 2/2/1) was refluxed for 2h, cooled, and filtered through Celite. The filtrate was evaporated and the residue 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 (5.28g, 100% yield).

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

To a solution of the product of part C at-20 deg.C (3.05g, 10mmol) in DMF (50ml) under nitrogen was added rapidly dropwise a 0.4M benzene solution of (E) -3-methoxyacryloyl isocyanate (50.0ml, 20.00mmol, prepared according to the method of Santana et al, J.Heterocyclic chem.36: 293 (1999)). The solution was stirred at-20 ℃ for 15min, warmed to room temperature, held for 45min and diluted with EtOAc. The organics were washed with water and brine. With Na₂SO₄Dried, filtered and concentrated to a brown solid. The residue was triturated with Et₂O/hexane to give a fine powder, which was collected by filtration and dried in vacuo to give the title compound as a brown powder (2.46g, 57%).

Part e. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H, 3H) -dione.

To a suspension of the product of part D (2.46g, 5.69mmol) in ethanol (50mL) was added 5.5mL of H₂SO₄50mL of an aqueous solution, and the mixture was heated at 110 ℃ for 2.5h to give a clear solution. Cooled, diluted with 50mL of water with stirring to give an off-white solid which was collected by filtration, washed with water and dried under vacuum to give the title compound (2.06g, 90%).

Part f. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

The product of part E (104mg, 0.26mmol), the product of example 2A, part B (108mg, 0.31mmol) and a 1: 1 ethanol-toluene (1) solution of 1.0M sodium carbonate (312. mu.L, 0.31mmol) were sparged with nitrogen in a microwave tube.7mL) the solution was degassed for 15 min. 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (9mg, 0.011mmol) was added, and degassing was continued for an additional 5 min. Sealing the tube, and heating with microwave at 100 deg.C for 1 h. Diluted with dichloromethane and washed with 1M citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for 1 h. Filter through Celite and concentrate in vacuo. Trituration with ether, methanol, then ether again gave the title compound as a near white solid (32mg, 25%).¹H NMR(300MHz，DMSO-d₆): δ 11.41(d, J ═ 1.84Hz, 1H)10.04(s, 1H)8.03(s, 1H)7.96(t, J ═ 8.09Hz, 2H)7.80(d, J ═ 8.09Hz, 1H)7.63-7.79(m, 2H)7.35-7.45(m, 1H)7.37(d, J ═ 2.57Hz, 1H)7.32(d, J ═ 2.57Hz, 1H)5.65(dd, J ═ 8.09, 2.21Hz, 1H)3.25(s, 3H)3.09(s, 3H)1.43(s, 9H). MS (+ ESI) m/z (relative enrichment): 494(100, M + H), 511(90, M + NH4), 987(20, 2M + H), 1009(8, 2M + Na).

EXAMPLE 3 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinolin-2-yl) methanesulfonamide (compound IB-L0-2.5).

Part a. preparation of (E) -N- (4-bromophenyl) -3-methoxyacrylamide.

4-Bromophenylamine (285mg, 1.659mmol) and CH were mixed₂Cl₂(2.0ml) and pyridine (0.25ml, 3.09mmol), and (E) -3-methoxyacryloyl chloride (200mg, 1.659mmol) was added slowly and stirred at room temperature for 2 h. The resulting yellow solid was filtered off and washed with water. The solid was dried in vacuo to give the title compound (406mg, 96%).

Part b. preparation of 6-bromoquinolin-2 (1H) -one.

The product of part A (395mg, 1.542mmol) was fractionatedIs added to H₂SO₄(4.5 ml). Stir at room temperature for 3h and pour onto crushed ice. The solid was filtered, washed with water and dried in vacuo to give the title compound (203mg, 59%).

Part c. preparation of 6-bromo-2-chloroquinoline.

To phosphorus oxychloride (2.5ml, 26.8mmol) was added portionwise the product of part B (200mg, 0.893 mmol). Reflux for 1h, cool to room temperature and pour onto crushed ice. With CHCl₃Extracting, mixing the extracts, and adding MgSO₄Drying, filtration and concentration in vacuo gave the title compound (173mg, 80%).

Part d. preparation of 6-bromo-2-aminoquinoline.

The product of part C (173mg, 0.713mmol), acetamide (843mg, 14.27mmol) and potassium carbonate (493mg, 3.57mmol) were combined and heated at 200 ℃ for 2 h. Cooling to room temperature and solidifying. Dissolved in CHCl₃And water. Aqueous layer with CHCl₃Extracting twice more, combining the extracts, washing with brine, and washing with Na₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with MeOH/CHCl₃Elution gave the title compound (92mg, 58%).

Part e. preparation of N- (6-bromoquinolin-2-yl) -N- (methylsulfonyl) methanesulfonamide.

The product of part D (90mg, 0.403mmol) and CH₂Cl₂(2.0ml) were mixed and triethylamine (0.062ml, 0.444mmol) and methanesulfonyl chloride (0.035ml, 0.444mmol) were added. Stirred at room temperature for 16 h. Triethylamine (0.062ml, 0.444mmol) and methanesulfonyl chloride (0.035ml, 0.444mmol) were added and stirred at room temperature for 1 h. Diluted with EtOAc, 10% citric acid, 10% NaHCO₃And a brine wash. With Na₂SO₄Drying, filtering and vacuum concentrating. Dissolved in EtOAc and poured into excess hexane. The solid was collected by filtration to give the title compound (94mg, 61%).

Part f. preparation of N- (methylsulfonyl) -N- (6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinolin-2-yl) methanesulfonamide.

The product of part E (94mg, 0.248mmol), bis (pinacolyl) diboron (94mg, 0.372mmol), potassium acetate (73.0mg, 0.744mmol),(6.22mg, 0.012mmol) and toluene (1.5ml) were mixed and refluxed for 18 h. Cool to room temperature, dilute with EtOAc and water, filter through Celite, separate the phases, and wash the organic phase with brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound (67mg, 63%).

Preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinolin-2-yl) methanesulfonamide.

The product of example 2B, part E (27mg, 0.067mmol), part F (37.4mg, 0.088mmol), ethanol (1.0ml), toluene (1.0ml) and 1M sodium carbonate (0.067ml, 0.067mmol) were mixed in a microwave tube and the solution degassed with nitrogen for 20 min. Tetrakis (triphenyl-phosphine) palladium (0) (1.559mg, 1.349 μmol) was added and the solution degassed an additional 5 min. Sealing the tube, and heating with microwave at 100 deg.C for 45 min. The solution was cooled, diluted with 1: 1 EtOAc: water and filtered through Celite. The aqueous layer was extracted twice more with EtOAc, and the organic extracts were combined and washed with brine. With Na ₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with MeOH/CHCl₃Elution gave the title compound (13.7mg, 41%).¹H NMR(300MHz，CDCl₃)δ1.45(s，9H)3.18(s，3H)3.30(s，3H)5.83(dd，J＝7.91，2.02Hz，1H)6.99(d，J＝8.82Hz，1H)7.21(d，J＝2.57Hz，1H)7.36(d，J＝7.72Hz，1H)7.52(d，J＝8.46Hz，1H)7.82-7.91(m，2H)7.98(d，J＝9.19Hz，1H)8.29(s，1H)；MS(ESI+)m/z495(M+H)⁺；(ESI-)m/z 493(M-H)^-。

EXAMPLE 4 preparation of (E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide (compound IB-L0-2.4).

Part a. preparation of 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one.

A mixture of 5-bromo-2, 3-dihydro-1H-inden-1-one (2.50g, 11.85mmol), bis (pinacolato) diboron (3.61g, 14.21mmol), potassium acetate (3.49g, 35.5mmol) and Combiphos Pd6(178mg, 0.36mmol) in toluene (60mL) was heated at reflux for 8H. Cool, dilute with EtOAc, extract with water (2 ×), wash with brine. With Na₂SO₄Dried and stirred with (3-mercaptopropyl) silica gel for 1 h. Filtration and concentration in vacuo afforded a yellow solid. Purification by silica gel column chromatography eluting with EtOAc/hexanes afforded a yellow solid. Trituration with cold hexanes, filtration, and vacuum drying afforded the title compound as a near white solid (1.99g, 65%). A second crop of crystals (140mg) was obtained from the mother liquor, giving a yield of 70%.

Part b. preparation of 1- (3-tert-butyl-4-methoxy-5- (1-oxo-2, 3-dihydro-1H-inden-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A suspension of the product of example 2B, part E (130mg, 0.33mmol), part A (101mg, 0.39mmol) and 1.0M sodium carbonate solution (390. mu.L, 0.39mmol) in 1: 1 ethanol-toluene (1.20mL) was degassed by nitrogen sparging in a microwave tube for 15 min. The mixture was treated with 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (13mg, 0.016mmol), degassed and then further heated for 5min with microwave at 100 ℃ for 1 h. Cooled, diluted with EtOAc, extracted with 1M citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for 1 h. Filtered and concentrated in vacuo. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound as a white solid (80mg, 61%).

Part c. preparation of (E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide.

A suspension of the product of part B (77mg, 0.19mmol) and methanesulfonyl hydrazide (22mg, 0.20mmol) in 3: 1 THF: MeOH (1.9mL) was heated at 60 deg.C for 24 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with EtOAc/hexanes to give the title compound as a white solid (62mg, 66%). ¹H NMR(300MHz，DMSO-d₆): δ 11.40(d, J ═ 1.84Hz, 1H)9.94(s, 1H)7.76(dd, J ═ 13.97, 8.09Hz, 2H)7.52-7.59(m, 1H)7.51(d, J ═ 8.46Hz, 1H)7.11-7.40(m, 2H)3.28(s, 3H)2.96-3.19(m, 5H), 2.85(m, 2H), 1.40(s, 9H). MS (+ ESI) m/z (relative enrichment): 497(100, M + H), 1015(5, 2M + Na).

Example 5 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-5-yl) methanesulfonamide (compound IB-L0-2.6).

Part a. preparation of methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.

Methyl 3, 5-di-tert-butyl-2-hydroxybenzoate (28.66g, 108.4mmol) was dissolved in 430mL of glacial acetic acid with stirring, and the resulting mixture was treated with dropwise fuming nitric acid (90%, 179.26 mL). When the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into 2.0L of crushed ice and left for 30 min. Then, 1.0L of water was added to melt the ice-water mixture. The mixture was then filtered, washed with water, and dried to provide the title compound (24.57g, 89%).

Part b. preparation of methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.

Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41g, 45.0mmol), potassium carbonate (9.34g, 67.6mmol), acetone (200mL) and methyl disulfate (6.46g, 67.6mmol) were added together. The resulting mixture was then heated to reflux for 16 h. The mixture was then filtered and the solid was washed with ethyl acetate. The resulting organic liquid was then concentrated in vacuo to an oil, which was redissolved in ethyl acetate (600 mL). The organic solution was then washed with water, dried, filtered, concentrated in vacuo to an oil, and then purified by column chromatography (5% to 40% EtOAc/hexanes gradient) to give the title compound as 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 (10.42g, 39.0mmol), iron powder (325 mesh, 10.89g, 195mmol), ammonium chloride (3.13g, 58.5mmol), water (30mL) and methanol (150mL) were added together. The resulting mixture was then refluxed for 1 h. The mixture was then cooled to room temperature, filtered through Celite, and the Celite was washed with methanol. The filtrate was then concentrated in vacuo and dissolved in ethyl acetate (600 mL). Then, the resulting solution was washed with water and brine. The organic extract was then dried, filtered, and concentrated in vacuo to give the title compound as an oil (9.25g, 100%).

Part d. preparation of methyl (E) -3-tert-butyl-2-methoxy-5- (3- (3-methoxyacryloyl) ureoyl) benzoate.

The product obtained in part C (2.0g, 8.43mmol) was dissolved in 30mL of N, N-dimethylacetamide and cooled to-25 ℃. A0.5M solution of E-3-methoxyacryloyl isocyanate in benzene (21.9mL, 10.96mmol) was added dropwise, and the resulting solution was stirred at ambient temperature for 4h, then poured into water. The product was extracted into dichloromethane, washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 100% yield.

Part e. preparation of methyl 3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxybenzoate.

The product of part D (3.1g, 8.51mmol) was dissolved in ethanol (60 mL). Sulfuric acid (6mL) was added to blast furnace water (60mL), and the solution was then added to ethanol in one portion. The heterogeneous mixture was heated at 100 ℃ for 3 h. The ethanol was removed under vacuum and the aqueous solution was then extracted with dichloromethane and evaporated to dryness. The residue was purified by flash chromatography, eluting with 1% methanol in dichloromethane, to give 1.23g (44%).

Part f. preparation of 3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxybenzoic acid.

The product of part E (1.23g, 3.7mmol) was treated in ethanol (5mL) and 1M sodium hydroxide solution (10mL) and stirred at ambient temperature for 18 h. The solution was diluted with 1M HCl and the resulting solid was filtered and dried to yield 0.945g (80%).

Part g. preparation of 3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxybenzaldehyde.

The product of part F (0.945g, 2.97mmol) was treated in thionyl chloride (4.5mL) and the mixture heated at 80 ℃ for 40 min. After evaporation to dryness, the acid chloride was dissolved in dry THF (8mL) and cooled to-78 ℃. A1M solution of lithium tri-tert-butoxyaluminum hydride in THF (3.0mL, 3.0mmol) was added dropwise. After 45min, the cold reaction was quenched with 1M HCl (5mL), extracted into ethyl acetate, purified by flash column eluting with dichloromethane then 1% methanol/dichloromethane to give 0.635g (71%).

Part H. preparation of 1- (3-tert-butyl-4-methoxy-5- (5-nitrobenzo [ d ] oxazol-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part G (400mg, 1.323mmol), 2-amino-4-nitrophenol (204mg, 1.323mmol), charcoal (Darco KB, 191mg, 15.88mmol) and toluene (50mL) were added to the flask and the mixture heated to 120 deg.C and stirred in air for 48 h. The mixture is filtered through the Celite to be filtered,and (4) concentrating in vacuum. Purifying by silica gel column chromatography with CH₂Cl₂MeOH to give the title compound (300mg, 52%).

Preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-5-yl) methanesulfonamide.

To the product of part H (300mg, 0.687mmol), iron (192mg, 3.44mmol) and ammonium chloride (55mg, 1.031mmol) was added a mixture of THF (15mL), EtOH (15mL) and water (4.5 mL). The resulting solution was heated to 90 ℃ for 45min and cooled. Filter through Celite, wash with ethanol, and concentrate in vacuo. The solid was dissolved in ethyl acetate and washed with water. With Na₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with CH₂Cl₂MeOH elution provided aniline. The solid (75mg, 0.185mmol) was dissolved in CH ₂Cl₂To (5mL) was added pyridine (0.045mL, 0.554mmol) and methanesulfonyl chloride (0.025mL, 0.323mmol), and the mixture was stirred at room temperature for 16 h. Adding CH₂Cl₂Then washed with 1N HCl. With Na₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with CH₂Cl₂MeOH elution provided the title compound as a solid (9.8mg, 3%, two steps).¹HNMR(300MHz，DMSO-d₆)：δ11.46(s，1H)，9.85(s，1H)，7.91(d，J＝2.2Hz，1H)，7.81(dd，J＝9.9，8.8Hz，2H)，7.68(d，J＝2.2Hz，1H)，7.56(d，J＝2.6Hz，1H)，7.33(dd，J＝8.8，1.8Hz，1H)，5.68(d，J＝7.7Hz，1H)，3.64(s，3H)，3.00(s，3H)，1.42(s，9H)。MS：m/z 485(M+H)+。

Example 6 preparation of 1- (3-tert-butyl-4-methoxy-5- (6-nitrobenzo [ d ] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4(1H, 3H) -dione (compound IA-L0-2.6).

Part a. preparation of 3- (3-tert-butyl-4-methoxy-5- (methoxycarbonyl) phenylamino) propionic acid.

The product of example 5, part C (16.44g, 69.3mmol) was dissolved in toluene (200 mL). The mixture was heated to reflux and acrylic acid was added in portions (1 mL of acrylic acid every 3h, 5.23mL total, 76.2 mmol). The mixture was then refluxed for 24 h. The mixture was then cooled and concentrated to dryness in vacuo to give an oil, the crude title compound, which was used directly in the next reaction.

Part b. preparation of methyl 3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoate.

The product of part A (21.43g, 69.3mmol), urea (10.4g, 173mmol) and acetic acid (ice, 200mL) were added together. The mixture was then heated to 120 ℃ for 18.5h, then concentrated in vacuo to dryness to an oil. To the oil were added methanol (13mL) and ethyl acetate (350 mL). The resulting mixture was left to stand for 24-48h to form a precipitate. The resulting solid was filtered, washed with a small amount of methanol (10mL), and then air-dried to give the title compound as a solid (15.26g, 66%).

Part c. preparation of 3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoic acid.

The product of part B (4.52g, 13.52mmol), methanol (70mL) and tetrahydrofuran (70mL) were added together. The mixture was then stirred vigorously until a homogeneous solution was formed. After homogenization, aqueous sodium hydroxide (1.0M, 68mL) was added. The mixture was then stirred for 12h, then the mixture was concentrated in vacuo to remove the organic solvent, then aqueous hydrochloric acid (1.0M, 80mL) was added, resulting in the formation of a solid. The mixture was then concentrated in vacuo. Hydrochloric acid (12M, 100mL) was added to the mass and the resulting mass was heated to 100 ℃ for 1.5 h. The reaction was then cooled and water was added. The resulting solid was filtered, washed with water and dried to give the title compound as a solid (3.55g, 82%).

Part d. preparation of 3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzaldehyde.

The product obtained in part C (4.07g, 12.71mmol) and thionyl chloride (40.82mL, 559mmol) were combined and the mixture refluxed for 2h then concentrated in vacuo to afford the product as a pale yellow solid. The solid was dissolved in tetrahydrofuran (125mL), the solution cooled to-78 deg.C and LiAl (OtBu) was added slowly over 10min ₃(1M, 14mL) while maintaining the temperature at-78 ℃. The mixture was stirred at 78 ℃ for 2 h. The reaction was quenched with hydrochloric acid (aq, 1M, 25mL) at-78 ℃. The mixture was warmed 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 half-saturated sodium bicarbonate solution. The organic layer was dried, filtered, and concentrated in vacuo to give the title compound as a solid (3.73g, 96%).

Part e. preparation of 1- (3-tert-butyl-4-methoxy-5- (6-nitrobenzo [ d ] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4(1H, 3H) -dione.

A mixture of the product of part D (75mg, 0.246mmol), 2-amino-5-nitrophenol (38mg, 0.0246mmol), and Darco KB charcoal (excess) was refluxed in toluene (10mL) for 24h under an oxygen atmosphere. Cooling, filtration and purification by reverse phase HPLC chromatography eluting with a gradient of 40-100% acetonitrile in water (0.1% TFA) afforded the title compound as a solid (96mg, 64%).¹H NMR(300MHz，DMSO-d₆)：δ1.42(s，9H)2.74(t，J＝6.80Hz，2H)3.66(s，3H)3.82-3.88(m，2H)7.56(d，J＝2.57Hz，1H)7.91(d，J＝2.57Hz，1H)8.09(d，J＝8.82Hz，1H)8.37(dd，J＝8.82，2.21Hz，1H)8.84(d，J＝2.21Hz，1H)10.44(s，1H)。MS ESI+(439)(M+H)+。

Example 7 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-6-yl) methanesulfonamide (compound IA-L0-2.5).

The product of example 6 (96 mg.0.219mmol) was reacted with iron (0.614g, 1.10mmol) and ammonium chloride (0.176g, 0.329mmol) in the presence of a mixture of tetrahydrofuran (5mL), ethanol (5mL) and water (3 mL). The slurry was heated to 90 ℃ for 45min and cooled to ambient temperature. Filter through a pad of Celite (10g), wash with ethanol (20mL), and concentrate the filtrate in vacuo to a solid. The resulting solid was dissolved in ethyl acetate and washed with water. With Na ₂SO₄Drying, filtration and concentration in vacuo afforded the corresponding aniline. The solid was dissolved in dichloromethane (10mL), pyridine (0.670mL, 0.657mmol) and methanesulfonyl chloride (0.221mL, 0.329mmol) were added and the solution was stirred at room temperature for 16 h. Adding CH₂Cl₂Then washed with 1N aqueous HCl. With Na₂SO₄Drying, filtering and vacuum concentrating. Purifying by silica gel column chromatography with 98: 2CH₂Cl₂MeOH elution afforded the title compound as a solid (25mg, 21%, two steps).¹H NMR(300MHz，DMSO-d₆)：δ1.41(s，9H)2.73(t，J＝6.62Hz，2H)3.06(s，3H)3.61(s，3H)3.83(t，J＝6.62Hz，2H)7.28(dd，J＝8.46，1.84Hz，1H)7.48(d，J＝2.57Hz，1H)7.65(d，J＝1.84Hz，1H)7.80(d，J＝1.47Hz，1H)7.82(d，J＝4.04Hz，1H)10.03(s，1H)10.41(s，1H)。MS ESI+(487)(M+H)+。

Example 8 preparation of 1- (3-tert-butyl-4-methoxy-5- (5-nitrobenzo [ d ] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4(1H, 3H) -dione (compound IA-L0-2.7).

The procedure of example 6, part E, was followed to combine the product of example 6, part D (150mg, 0.493mmol) with 2-ammoniaReaction of yl-4-nitrophenol (76mg, 0.493mmol) provided the title compound as a solid (70mg, 32%).¹H NMR(300MHz，DMSO-d₆)：δ1.42(s，9H)2.74(t，J＝6.80Hz，2H)3.65(s，3H)3.85(t，J＝6.62Hz，2H)7.55(d，J＝2.57Hz，1H)7.89(d，J＝2.94Hz，1H)8.12(d，J＝8.82Hz，1H)8.40(dd，J＝9.01，2.39Hz，1H)8.76(d，J＝2.21Hz，1H)10.43(s，1H)。MS ESI+(439)(M+H)+。

Example 9 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-5-yl) methanesulfonamide (compound IA-L0-2.8).

The product of example 8 (65mg, 0.148mmol) was reacted according to the procedure for example 7 to provide the title compound as a solid (42mg, 44%). ¹H NMR(300MHz，DMSO-d₆)：δ1.41(s，9H)2.73(t，J＝6.43Hz，2H)3.01(s，3H)3.60(s，3H)3.83(t，J＝6.43Hz，2H)7.31(dd，J＝8.64，2.02Hz，1H)7.49(d，J＝2.94Hz，1H)7.56(d，J＝2.21Hz，1H)7.67(d，J＝2.21Hz，1H)7.81(s，1H)9.82(s，1H)10.41(s，1H)。MS ESI+(487)(M+H)+。

EXAMPLE 10 preparation of 1- (3- (benzo [ d ] thiazol-2-yl) -5-tert-butyl-4-methoxyphenyl) dihydropyrimidine-2, 4(1H, 3H) -dione (compound IA-L0-2.3).

The procedure of example 6, part E, was followed, using the product of example 6, part D (75mg, 0.246mmol) and 2-aminobenzenethiol (0).026mL, 0.246mmol) to afford the title compound as a solid (25mg, 25%).¹H NMR(300MHz，DMSO-d₆)：δ1.44(s，9H)2.73(t，J＝6.43Hz，2H)3.62(s，3H)3.84(t，J＝6.62Hz，2H)7.46(d，J＝2.57Hz，1H)7.48-7.60(m，2H)7.86(d，J＝2.57Hz，1H)8.13(dd，J＝17.28，7.72Hz，2H)10.40(s，1H)。MS ESI+(410)(M+H)+。

EXAMPLE 11 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-benzo [ d ] imidazol-5-yl) methanesulfonamide (Compound IA-L0-2.1).

Part a. preparation of N- (3, 4-dinitrophenyl) methane sulfonamide.

3, 4-dinitroaniline (5.27g, 28.8mmol), methanesulfonyl chloride (3.36mL, 43.1mmol) and pyridine (5.82mL, 71.9mmol) in CH₂Cl₂The mixture was stirred (100mL) for 24 h. The mixture was concentrated in vacuo to afford the title compound as a crude semi-solid, which was used without further purification.

Part b. preparation of N- (3, 4-diaminophenyl) methanesulfonamide.

Product of part A (7.51g, 28.8mmol) with iron (16g, 288mmol) and NH₄Cl (3.84g, 71.9mmol) in refluxing CH₃OH (100mL) and water (20mL) for 2 h. Filter through Celite and concentrate in vacuo. Purifying by silica gel column chromatography with MeOH/CH ₂Cl₂Elution provided the title compound as a dark semi-solid (0.5g, 8%).

Preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-benzo [ d ] imidazol-5-yl) methanesulfonamide.

According to example 6, part EProcedure, example 6, part D product (200mg, 0.657mmol) and part B product (132mg, 0.657mmol) were reacted to provide the title compound as a solid (112mg, 34%).¹H NMR(300MHz，DMSO-d₆)：δ1.43(s，9H)2.72(t，J＝6.62Hz，2H)2.93(s，3H)3.44(s，3H)3.82(t，J＝6.43Hz，2H)7.07-7.14(m，1H)7.38(d，J＝2.57Hz，1H)7.48-7.64(m，2H)7.72(d，J＝2.57Hz，1H)9.57(s，1H)10.38(s，1H)12.55(s，1H)。MS ESI+(486)(M+H)+。

EXAMPLE 12 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-6-yl) methanesulfonamide (Compound IA-L0-2.2).

Part a. preparation of N- (3-chloro-4-nitrophenyl) methanesulfonamide.

A mixture of 3-chloro-4-nitroaniline (4.85g, 28.1mmol), methanesulfonyl chloride (3.29mL, 42.2mmol) and pyridine (6.82mL, 84mmol) in THF (100mL) was stirred for 24 h. Pour in 1M HCl (500 mL). The resulting precipitate was filtered and air dried to provide the title compound as a solid (7.03g, 100%).

Part B preparation of N- (3- (4-methoxybenzylthio) -4-nitrophenyl) methanesulfonamide.

The product of part A (7.0g, 27.9mmol), (4-methoxyphenyl) methanethiol (3.89mL, 27.9mmol) and K ₂CO₃A mixture of (11.58g, 84mmol) DMF was heated at 100 ℃ for 12 h. Cooled and poured into 1M HCl (800 mL). The resulting precipitate was filtered and air dried to provide the title compound as a yellow solid (6.98g, 68%).

Part c. preparation of N- (4-amino-3- (4-methoxybenzylthio) phenyl) methanesulfonamide.

The product of part B (6.98g, 19.0mmol) was reacted according to the procedure for example 11, part B, to provide the title compound as a yellow semi-solid (4.44g, 69%).

Part d. preparation of N, N '- (3, 3' -disulfanediylbis (4-amino-3, 1-phenylene)) dimethanesulfonamide.

The product of part C (708mg, 2.09mmol) was reacted with mercury (II) acetate (667mg, 2.09mmol), anisole (0.457mL, 4.18mmol) and TFA (10mL) at 0 deg.C for 45 min. Concentrate in vacuo and dissolve in MeOH. Hydrogen sulfide gas was bubbled into the solution for 1h, then filtered and concentrated in vacuo. Purification by silica gel chromatography eluting with EtOAc/hexanes afforded the title compound as a yellowish solid (340mg, 75%).

Part e. preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-6-yl) methanesulfonamide.

The product of part D (100mg, 0.23mmol) was reacted with the product of part D of example 6 (140mg, 0.46mmol), triphenylphosphine (60.4mg, 0.23mmol) and 4-methylbenzenesulfonic acid (0.0054mL, 0.046mmol) in refluxing toluene for 3 h. Concentrated in vacuo and purified by reverse phase HPLC chromatography eluting with a gradient of 40-100% acetonitrile in water (0.1% TFA) to give the title compound as a solid (99mg, 43%). ¹H NMR(300MHz，DMSO-d₆)：δ1.43(s，9H)2.73(t，J＝6.62Hz，2H)3.07(s，3H)3.63(s，3H)3.83(t，J＝6.62Hz，2H)7.39(dd，J＝8.82，2.21Hz，1H)7.45(d，J＝2.57Hz，1H)7.83(d，J＝2.57Hz，1H)7.95(d，J＝2.21Hz，1H)8.05(d，J＝8.82Hz，1H)10.03(s，1H)10.39(s，1H)。MS ESI+(503)(M+H)+。

EXAMPLE 13 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-5-yl) methanesulfonamide (Compound IA-L0-2.4).

Part a. preparation of N- (4-chloro-3-nitrophenyl) methanesulfonamide.

A mixture of 4-chloro-3-nitroaniline (5.0g, 29mmol), methanesulfonyl chloride (2.37mL, 30.4mmol) and pyridine (5.9mL, 72.4mmol) in THF (100mL) was stirred for 24 h. Pour into 1M HCl (500 mL). The resulting precipitate was filtered and air dried to provide the title compound as a solid (6.7g, 92%).

Part B preparation of N- (4- (4-methoxybenzylthio) -3-nitrophenyl) methanesulfonamide.

The product of part A (3.0g, 12mmol), (4-methoxyphenyl) methanethiol (1.67mL, 12mmol) and K₂CO₃A mixture of (4.96g, 36mmol) DMF was heated at 100 ℃ for 12 h. Cool and pour into 1M HCl (800 mL). The resulting precipitate was filtered and air dried to provide the title compound as a yellow solid (1.95g, 44.2%).

Part c. preparation of N- (3-amino-4- (4-methoxybenzylthio) phenyl) methanesulfonamide.

Following the procedure of example 11, part B product (1.43g, 3.88mmol) was reacted to provide the title compound as a white solid (1.31g, 100%).

Part d. preparation of N, N '- (4, 4' -disulfanediylbis (3-amino-4, 1-phenylene)) dimethanesulfonamide.

The product of part C (75mg, 0.222mmol) was reacted with mercury (II) acetate (70.6mg, 0.222mmol), anisole (0.048mL, 0.443mmol) and TFA (10mL) at 0 deg.C for 45 min. Concentrate in vacuo and dissolve in MeOH. Hydrogen sulfide gas was bubbled into the solution for 1h, then filtered and concentrated in vacuo. Purification by column chromatography on silica eluting with EtOAc/hexanes afforded the title compound as a yellowish solid (34mg, 71%).

Part e. preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-5-yl) methanesulfonamide.

The product of part D (50mg, 0.115mmol) was reacted with the product of part D (70mg, 0.230mmol), triphenylphosphine (30.2mg, 0.115mmol) and 4-methylbenzenesulfonic acid (0.00267mL, 0.023mmol) from example 6 in refluxing toluene for 3 h. Concentrated in vacuo and purified by reverse phase HPLC chromatography eluting with a gradient of 40-100% acetonitrile in water (0.1% TFA) to give the title compound as a solid (40mg, 33%).¹H NMR(300MHz，DMSO-d₆)：δ1.43(s，9H)2.73(t，J＝6.80Hz，2H)3.05(s，3H)3.63(s，3H)3.84(t，J＝6.62Hz，2H)7.35(dd，J＝8.64，2.02Hz，1H)7.46(d，J＝2.94Hz，1H)7.86(d，J＝2.94Hz，1H)7.92(d，J＝1.84Hz，1H)8.10(d，J＝8.46Hz，1H)9.98(s，1H)10.40(s，1H)。MS ESI+(503)(M+H)+。

EXAMPLE 14 preparation of 1- (3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.1).

Part a. preparation of tert-butyl 3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) phenylcarbamate.

A solution of the product of example 1, part H (200mg, 0.56mmol), naphthalene-2-boronic acid (144mg, 0.84mmol) and 1.0M sodium carbonate solution (558. mu.L, 0.56mmol) in toluene (2.8mL) was degassed by nitrogen sparging in a resealable Schlenk tube for 10 min. The mixture was treated with 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (14mg, 0.017mmol) and degassing was continued for a further 5 min. The Schlenk tube was sealed and heated at 95 ℃ for 18 h. Cool and dilute with ethyl acetate and water. Treated with Darco G-60 and filtered through Celite. The filtrate was extracted with water (2 ×) and brine. With Na₂SO₄Drying, filtering and concentrating. Purifying by silica gel column chromatography, eluting with 10-75% EtOAc in hexane,the title compound was obtained as an oil (210mg, 93%).

Part b. preparation of 3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) aniline.

The product of part a (210mg, 0.52mmol) was dissolved in 4n hcl in dioxane (4.0mL) and stirred at room temperature for 1 h. Concentrate in vacuo to afford a solid, suspend in ethyl acetate and stir with saturated sodium bicarbonate solution. Na for organic layer₂SO₄Drying, filtration and concentration in vacuo gave the title compound as a brown oil (111mg, 70%).

Part c preparation of (E) -N- (3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) phenylcarbamoyl) -3-methoxyacrylamide.

A solution of the product of part B (111mg, 0.36mmol) at-20 deg.C in dry DMF (2.9mL) was treated with a solution of (E) -3-methoxyacryloyl isocyanate (0.66mL, 0.55M in benzene, 0.36mmol) and then gradually warmed to room temperature. After stirring for 30min, the mixture was cooled again to-20 ℃ and more (E) -3-methoxyacryloyl isocyanate solution (1.0mL, 0.55mmol) was added. After further warming to room temperature for 30min, the reaction was complete. Diluted with EtOAc, extracted with water and brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by silica gel column chromatography eluting with 10-100% EtOAc in hexane afforded the title compound as a pale yellow oil (144mg, 92%).

Part d. preparation of 1- (3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A suspension of the product of part C (144mg, 0.33mmol) in 2: 1 ethanol-water-THF (15mL) was treated with a 1N solution of sulfuric acid (3.0mL) and then heated at 100 ℃ for 24 h. Cool, dilute with EtOAc, extract with water and brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by silica gel column chromatography eluting with 10-100% EtOAc in hexane afforded the title compound as a white solid (62mg, 47%). ¹H NMR(300MHz，DMSO-d₆)：δ11.42(s，1H)，8.08(s，1H)，7.90-8.04(m，3H) 7.81(d, J ═ 7.72Hz, 1H), 7.72(d, J ═ 8.46Hz, 1H), 7.56(dd, J ═ 6.25, 3.31Hz, 2H), 7.39(d, J ═ 2.57Hz, 1H), 7.33(d, J ═ 2.57Hz, 1H), 5.65(d, J ═ 7.72Hz, 1H), 3.24(s, 3H), 1.43(s, 9H). MS + ESI m/z (relative enrichment): 401(100, M + H), 418(30, M + NH 4).

EXAMPLE 15 preparation of 1- (3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.2).

Part a. preparation of tert-butyl 3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) phenylcarbamate.

The product of example 1, part H (158mg, 0.44mmol) was reacted with 6-methoxy-naphthalen-2-ylboronic acid (107mg, 0.52mmol) according to the procedure of example 14, part A, to provide the title compound as a white solid (92mg, 47%).

Part b. preparation of 3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) aniline.

The product of part a (92mg, 0.21mmol) was reacted according to the procedure of example 14, part B, to provide the title compound as a pink solid (71mg, 99%).

Part c preparation of (E) -N- (3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) phenylcarbamoyl) -3-methoxyacrylamide.

The product of part B (71mg, 0.21mmol) was reacted according to the procedure for example 14, part C, to provide the title compound as a pale yellow solid (58mg, 59%).

Part d. preparation of 1- (3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A2: 1 ethanol-THF-water (4.0mL) solution of the product of part C (58mg, 0.13mmol) was treated with 1.0M sulfuric acid solution (3.0mL) and then heated at 95 ℃ for 24 h. Cool and dilute with EtOAc. Extracting with water and brine. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by silica gel column chromatography eluting with 10-100% EtOAc in hexane afforded the product as a pale pink solid (28mg, 52%).¹H NMR(300MHz，DMSO-d₆): δ 11.41(s, 1H), 8.00(s, 1H), 7.91(dd, J ═ 8.64, 4.60Hz, 2H), 7.80(d, J ═ 7.72Hz, 1H), 7.67(d, J ═ 8.82Hz, 1H), 7.34-7.47(m, 2H), 7.21-7.32(m, 1H), 7.20(dd, J ═ 9.01, 2.39Hz, 1H), 5.65(d, J ═ 7.72Hz, 1H), 3.90(s, 3H), 3.24(s, 3H), 1.42(s, 9H). MS + ESI m/z (relative enrichment): 431(100, M + H), 448(45, M + NH 4).

EXAMPLE 16 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.8).

Part a. preparation of 2-bromo-4-tert-butyl-6-nitroaniline.

A suspension of 4-tert-butyl-2-nitroaniline (1.033g, 5.32mmol) in glacial acetic acid (7.8mL) was heated with a heat gun until all the solid had dissolved. The solution was then cooled and treated with pyridinium tribromide (1.96g, 6.12mmol) in portions. After the addition, the solution was stirred at room temperature for 1 h. The mixture was added to water (50mL) and treated with a small amount of sodium sulfite. After stirring for 30min, the precipitate was collected by filtration. The resulting solid was washed with water and dissolved in EtOAc. Washed with water and brine. With Na₂SO₄Drying, filtration, and concentration in vacuo afforded the title compound as a yellow-orange solid (1.36g, 94%).

Part b. preparation of 1-bromo-3-tert-butyl-5-nitrobenzene.

A solution of tert-butyl nitrite (300. mu.L 90%, 261mg, 2.27mmol) in dry DMF (4mL) was heated at 50 ℃ and treated with a solution of the product of part A (414mg, 1.52mmol) in DMF (3.5 mL). After a few minutes of stirring, the solution started to foam vigorously. After heating at 50 ℃ for 1h, additional (300. mu.L) tert-butyl nitrite was added, followed by heating at 50 ℃ for 1 h. After 18h at room temperature, tert-butyl nitrite (1.2mL) was added and the mixture was heated at 50 ℃ for 2 h. Cool and dilute with EtOAc. Washed with water and brine. With Na ₂SO₄Drying, filtering and vacuum concentrating. Purification by column chromatography on silica gel eluting with 5-40% ethyl acetate in hexane afforded the title compound as a pale yellow oil (159mg, 41%).

Part c. preparation of 3-bromo-5-tert-butylaniline.

A solution of the product of part B (770mg, 2.98mmol) in 3: 1 methanol-water-THF (14.9mL) was treated with ammonium chloride (239mg, 4.47mmol) and iron powder (833mg, 14.92mmol) and then heated at reflux for 8 h. Diluted with EtOAc and water and filtered through Celite. The filtrate was extracted with water and brine. With Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound as a yellow oil.

Part d. preparation of (E) -N- (3-bromo-5-tert-butylphenyl carbamoyl) -3-methoxyacrylamide.

A solution of the product of part C at-30 deg.C (681mg, 2.99mmol) in dry DMF (23mL) was treated with a dropwise addition of 0.4M (E) -3-methoxyacryloyl isocyanate in benzene (14.9mL, 5.96 mmol). The solution was stirred at-30 ℃ for 30min, then gradually warmed to room temperature, and then stirred for 18 h. Dilute with EtOAc, wash with water and brine. With Na₂SO₄Drying, filtration, and concentration in vacuo afforded a yellow solid, triturated with ether-hexane, collected by filtration. Drying in vacuo afforded the title compound as a pale brown powder (951mg, 90%).

Part e. preparation of 1- (3-bromo-5-tert-butylphenyl) pyrimidine-2, 4(1H, 3H) -dione.

A suspension of the product of part D (951mg, 2.68mmol) in ethanol (25mL) was treated with a solution of concentrated sulfuric acid (2.60mL, 4.78g, 18.22mmol) in water (13.4mL) and then heated at 100 ℃ for 1 h. Cooling, concentrating to remove ethanol. Cooled to 0 ℃, the precipitate was collected by filtration and washed with water. Drying in vacuo afforded the title compound as an orange solid (619mg, 72%).

Part f. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide.

A suspension of the product of part E (104mg, 0.32mmol), the product of example 2A, part B (134mg, 0.39mmol) and 1.0M sodium carbonate solution (386. mu.L, 0.39mmol) in 1: 1 ethanol-toluene (2.1mL) was degassed by nitrogen sparging in a microwave tube for 10 min. The solution was treated with 1, 1' -bis (di-tert-butylphosphino) ferrocene-palladium (II) dichloride (20mg, 0.031mmol) and degassing was continued for an additional 5 min. The mixture was heated at 100 ℃ for 30min with a microwave. Dilute with EtOAc, wash with water and brine. With Na₂SO₄Dried and treated with (3-mercaptopropyl) silica gel for 30 min. Filtration and concentration in vacuo afforded an amber solid, which was triturated with ether-hexane. The solid was collected by filtration and dried in vacuo to provide the title compound (81mg, 54%). ¹H NMR(300MHz， DMSO-d₆)：δ11.46(s，1H)10.05(s，1H)，8.25(s，1H)7.98(dd，J＝11.58，9.01Hz，1H)7.86-7.93(m，1H)7.78-7.85(m，2H)7.72(s，1H)7.67(s，1H)7.31-7.51(m，2H)5.70(dd，J＝7.72，2.21Hz，1H)3.08(s，3H)1.39(s，9H)。

EXAMPLE 17 preparation of (E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide (compound IB-L0-2.7).

Part a. preparation of 1- (3-tert-butyl-5- (1-oxo-2, 3-dihydro-1H-inden-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A suspension of the product of example 16, part E, the product of example 4, part A (144mg, 0.56mmol), 1.0M sodium carbonate solution (557 μ L, 0.56mmol) in 1: 1 ethanol-toluene (3.0mL) was degassed by nitrogen sparging in a microwave tube for 15 min. 1, 1' -bis (di-tert-butylphosphino) ferrocene palladium (II) chloride complex (15mg, 0.023mmol) was added and degassing was continued for an additional 5 min. The tube was sealed and the mixture was microwave heated at 100 ℃ for 30 min. Dilute with EtOAc and water. Washed with 1M citric acid solution, water and brine. The organic was stirred with (3-mercaptopropyl) silica gel for 1 h. With Na₂SO₄Drying, filtering and vacuum concentrating. Purification by column chromatography on silica eluting with 10-100% EtOAc in hexane afforded the title compound as an off-white solid (86mg, 50%).

Part b. preparation of (E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide.

The product of part A (80mg, 0.21mmol) was reacted according to the procedure of example 4, part C, to provide the title compound as a white solid (73mg, 73%).¹H NMR(300MHz，DMSO-d₆): δ 11.44(s, 1H)9.92(s, 1H)7.64-7.98(m, 5H)7.57(s, 1H)7.45(s, 1H)5.68(d, J ═ 7.72Hz, 1H)3.00-3.20(m, 5H)2.85(d, J ═ 12.50Hz, 2H)1.36(s, 9H). MS + ESI m/z (relative enrichment): 467(100, M + H).

EXAMPLE 18 preparation of N- (6- (3-bromo-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.69).

Part a. preparation of 2-bromo-4, 6-diiodophenol.

To a 1L round bottom flask were added 2-bromophenol (Aldrich, 8.65g, 50mmol) and methanol (100mL) to give a colorless solution. Sodium hydroxide (2.40g, 60.0mmol) was added and stirred until the hydroxide pellets had dissolved. The solution was cooled in an ice-water bath, sodium iodide (5.6g, 37.4mmol) was added, and then sodium hypochlorite (17mL, 27.5mmol) was added dropwise to give a clear brown/red solution, gradually precipitating as a viscous white solid. The addition of sodium iodide and bleaching agent was repeated 3 times to give an orange mixture, which was stirred for 2h, treated with a solution of sodium thiosulfate in water (20g, 100mL), stirred for 15min, and treated with dropwise concentrated HCl to a constant pH of 1. The mixture was stirred for 15min, the white solid collected by filtration, washed repeatedly with water and dried to constant weight (14.7g, 69%).

Part b. preparation of 1-bromo-3, 5-diiodo-2-methoxybenzene.

To a 500mL round bottom flask was added the product of part A (14.7g, 34.6mmol), methyl iodide (2.70mL, 43.3mmol) and sodium hydroxide (2.101mL, 39.8mmol) in acetone (96mL) to give a brown solution. The mixture was stirred for 24h 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 which was collected by filtration (12.3g, 81%).

Part c. preparation of 1- (3-bromo-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a 250mL round bottom flask was added the product of part B (8.09g, 18.44mmol), pyrimidine-2, 4(1H, 3H) -dione (2.273g, 20.28mmol), N- (2-cyanophenyl) picolinamide (0.823g, 3.69mmol), copper (I) iodide (0.351g, 1.844mmol) and potassium phosphate (8.22g, 38.7mmol) in DMSO (70 mL). The mixture was sealed, sparged with nitrogen for 15min and heated at 60 ℃ for 16 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with 1M HCl, water, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel (Aldrich catalog #538086), filtered through Celite and evaporated to give an off-white solid (3.92g, 50%).

Part d. preparation of N- (6- (3-bromo-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

To a 5mL microwave tube was added a solution of the product of part C (212mg, 0.50mmol), the product of example 2A, part B (174mg, 0.50mmol), potassium phosphate (223mg, 1.05mmol), PA-Ph (CAS 97739-46-3, 4.38mg, 0.015mmol), and tris (dibenzylideneacetone) dipalladium (0) (4.58mg, 5.00. mu. mol) in tetrahydrofuran (3.0mL) and water (1.0 mL). The tube was sealed and the mixture sparged with nitrogen for 5min, then stirred for 24 h. The reaction mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel (Aldrich catalog #538086), filtered through Celite and evaporated. The residue is taken up in methanol/CH₂Cl₂Trituration afforded the title compound as a white solid (256mg, 51%).¹H NMR(300MHz，DMSO-d₆)δppm 3.08(s，3H)3.43(s，3H)5.68(d，J＝8.09Hz，1H)7.43(dd，J＝8.82，2.21Hz，1H)7.60(d，J＝2.57Hz，1H)7.72(m，2H)7.82(d，J＝3.31Hz，1H)7.84(d，J＝1.84Hz，1H)7.96(m，2H)8.09(s，1H)10.07(s，1H)11.49(s，1H)。MS(ESI-)m/z 513.9，515.9(M-H)⁺。

EXAMPLE 19 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (5-methylfuran-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.58).

To a 5mL microwave tube were added the product of example 18 (52mg, 0.101mmol), 4, 5, 5-tetramethyl-2- (5-methyl) Furan-2-yl) -1, 3, 2-dioxaborolan (0.025ml, 0.121mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (3.28mg, 5.04. mu. mol) and potassium phosphate (42.8mg, 0.201mmol) in THF (3.0ml) and water (1.0 ml). The tube was sealed and the mixture sparged with nitrogen for 5min and then heated at 50 ℃ for 3 h. The mixture was cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified by reverse phase chromatography to give the desired product as a white solid (23mg, 44%, m.p.174-178 ℃ C.)¹H NMR(300MHz，DMSO-d₆)δppm 2.38(s，3H)3.09(s，3H)3.33(s，3H)5.69(dd，J＝7.72，2.21Hz，1H)6.30(d，J＝3.31Hz，1H)7.00(d，J＝3.31Hz，1H)7.43(m，2H)7.74(d，J＝2.57Hz，2H)7.78(dd，J＝8.46，1.84Hz，1H)7.85(d，J＝8.09Hz，1H)7.97(t，J＝8.82Hz，2H)8.12(s，1H)10.05(s，1H)11.46(d，J＝2.21Hz，1H)。MS(ESI+)m/z518(M+H)⁺。

EXAMPLE 20 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-3-yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.53).

The title compound was prepared according to the procedure for example 19 substituting thiophen-3-ylboronic acid for 4, 4, 5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan to give a white solid (12mg, 23%).¹H NMR(300MHz，DMSO-d₆)δppm 3.07(s，3H)3.22(s，3H)5.69(d，J＝7.72Hz，1H)7.41(dd，J＝8.64，2.02Hz，1H)7.50(d，J＝2.94Hz，1H)7.59(dd，J＝5.13，1.08Hz，1H)7.69(m，3H)7.76(dd，J＝8.64，1.65Hz，1H)7.89(d，J＝7.72Hz，1H)7.95(m，3H)8.09(s，1H)10.05(s，1H)11.47(s，1H)。MS(ESI+)m/z520(M+H)⁺。

EXAMPLE 21 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.61).

The title compound was prepared according to the procedure for example 19 substituting thiophen-2-ylboronic acid for 4, 4, 5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan to give a white solid (8mg, 15%).¹H NMR(300MHz，DMSO-d₆)δppm 3.08(s，3H)3.30(s，3H)5.70(d，J＝8.09Hz，1H)7.19(dd，J＝5.33，3.86Hz，1H)7.42(dd，J＝8.82，2.21Hz，1H)7.49(d，J＝2.57Hz，1H)7.69(dd，J＝5.15，1.20Hz，1H)7.80(m，3H)7.88(d，J＝7.72Hz，1H)7.92(d，J＝2.57Hz，1H)7.98(m，2H)8.12(s，1H)10.06(s，1H)11.48(s，1H)。MS(ESI+)m/z520(M+H)⁺。

EXAMPLE 22 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.59).

The title compound was prepared according to the procedure for example 19 substituting furan-2-ylboronic acid for 4, 4, 5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan to give a white solid (16mg, 32%).¹H NMR(300MHz，DMSO-d₆)δppm 3.09(s，3H)3.35(s，3H)5.69(d，J＝7.72Hz，1H)6.69(dd，J＝3.31，1.84Hz，1H)7.11(d，J＝3.31Hz，1H)7.43(dd，J＝8.82，2.21Hz，1H)7.49(d，J＝2.94Hz，1H)7.80(m，5H)7.96(m，2H)8.13(s，1H)10.06(s，1H)11.47(s，1H)。MS(ESI-)m/z502.1(M-H)⁺。

EXAMPLE 23 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.64).

The title compound was prepared according to the procedure for example 19 substituting furan-3-ylboronic acid for 4, 4, 5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan to give a white solid (6mg, 12%).¹H NMR(300MHz，DMSO-d₆)δppm 3.09(s，3H)3.30(s，3H)5.69(dd，J＝7.71，1.83Hz，1H)7.10(dd，J＝1.74，0.78Hz，1H)7.42(dd，J＝8.82，2.21Hz，1H)7.46(d，J＝2.57Hz，1H)7.73(d，J＝2.21Hz，1H)7.76(d，J＝2.57Hz，1H)7.78(d，J＝1.84Hz，1H)7.81(t，J＝1.84Hz，1H)7.86(d，J＝7.72Hz，1H)7.96(t，J＝8.82Hz，2H)8.10(s，1H)8.28(s，1H)10.05(s，1H)11.48(s，1H)。MS(ESI-)m/z502.1(M-H)⁺。

EXAMPLE 24 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-biphenyl-3-yl) naphthalen-2-yl) methanesulfonamide (Compound IB-L0-2.71).

The title compound was prepared according to the procedure for example 19 substituting phenylboronic acid for 4, 4, 5, 5-tetramethyle2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan. The crude product was purified by chromatography on silica gel using 3% methanol/CH₂Cl₂Elution gave a white solid (10mg, 8%).¹H NMR(300MHz，DMSO-d₆)δppm 3.08(s，3H)3.12(s，3H)5.69(dd，J＝7.81，1.47Hz，1H)7.36(m，5H)7.56(d，J＝2.57Hz，1H)7.64(m，2H)7.74(d，J＝2.21Hz，1H)7.78(dd，J＝8.46，1.84Hz，1H)7.94(m，3H)8.11(s，1H)10.04(s，1H)11.47(s，1H)。MS(ESI-)m/z512(M-H)⁺。

EXAMPLE 25 preparation of N- (6- (3' -chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxybiphenyl-3-yl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.74).

The title compound was prepared according to the procedure for example 19 substituting 3-chlorophenylboronic acid for 4, 4, 5, 5-tetramethyl-2- (5-methylfuran-2-yl) -1, 3, 2-dioxaborolan to give a white solid (38mg, 68%).¹H NMR(300MHz，DMSO-d₆)δppm 3.09(s，3H)3.13(s，3H)5.70(dd，J＝8.09，2.21Hz，1H)7.43(dd，J＝8.82，2.21Hz，1H)7.52(m，3H)7.62(m，2H)7.72(m，2H)7.79(dd，J＝8.46，1.47Hz，1H)7.95(m，3H)8.12(s，1H)10.05(s，1H)11.47(d，J＝2.21Hz，1H)。MS(ESI-)m/z546(M-H)⁺。

EXAMPLE 26 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (5-methylthiophen-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.73).

The title compound was prepared according to the procedure for example 19 substituting 4, 4, 5, 5-tetramethyl-2- (5-methylthiophen-2-yl) -1, 3, 2-dioxaborolan for 4, 4, 5, 5-tetramethyl-2- (5-methyl-furan-2-yl) -1, 3, 2-dioxaborolan to give a white solid (22mg, 41%).¹H NMR(300MHz，DMSO-d₆)δppm 2.49(s，3H)3.09(s，3H)3.29(s，3H)5.69(dd，J＝8.09，2.21Hz，1H)6.87(d，J＝2.57Hz，1H)7.43(m，2H)7.54(d，J＝3.68Hz，1H)7.76(m，2H)7.85(s，1H)7.87(d，J＝5.15Hz，1H)7.98(t，J＝9.01Hz，2H)8.11(s，1H)10.06(s，1H)11.47(d，J＝2.21Hz，1H)。MS(ESI+)m/z534(M+H)⁺。

EXAMPLE 27 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan-2-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.54).

Part a. preparation of 2- (2-hydroxy-3, 5-diiodophenyl) acetic acid.

A250 mL round bottom flask was charged with a solution of 2- (2-hydroxyphenyl) acetic acid (Aldrich, 3.04g, 20mmol) in acetonitrile (50mL) to give a colorless solution. N-iodosuccinimide (9.00g, 40.0mmol) was added portionwise over 15min to give a red/brown clear solution which was stirred for 16 h. The mixture was concentrated and the resulting solid was triturated in 75mL water, collected by filtration as an orange solid and dried in vacuo. The crude solid was recrystallized from toluene to give a pale orange powder (6.0g, 74%).

Part b. preparation of methyl 2- (3, 5-diiodo-2-methoxyphenyl) acetate.

To a 250mL round bottom flask was added the product of part A (6g, 14.85mmol), potassium carbonate (6.16g, 44.6mmol) and bisA solution of methyl sulfate (4.12g, 32.7mmol) in acetone (49.5mL) gave a brown suspension. Heated at reflux for 16h, cooled, concentrated and the residue partitioned between EtOAc and water. The EtOAc layer was washed with brine and dried (Na)₂SO₄) Concentrated to a brown oil, chromatographed on a 40g silica gel column eluting with 3: 1 hexane/EtOAc to give a yellow oil (6.0g, 94%).

Part c. preparation of methyl 2- (3, 5-diiodo-2-methoxyphenyl) -2-methylpropionate.

A100 mL round-bottom flask was charged with a solution of the product of part B (1.728g, 4mmol) in anhydrous THF (20mL) and HMPA (2mL) under nitrogen to give a colorless solution. Methyl iodide (1.251ml, 20.00mmol) was added and the solution cooled to-40 ℃. Potassium tert-butoxide (12.00ml, 12.00mmol) was added dropwise, the mixture was stirred at-40 to-20 ℃ for 30min and quenched with 1M HCl to pH 1. The mixture was extracted with 3X 40ml EtOAc. The combined extracts were washed with brine and dried (Na) ₂SO₄) And (4) concentrating. The crude product was flash chromatographed on a 40g ISCO silica gel column, eluting with 9: 1 hexanes/EtOAc to give the bis-methylated product as a yellow oil (1.63g, 89%).

Part d. preparation of 2- (3, 5-diiodo-2-methoxyphenyl) -2-methylpropionic acid.

A suspension of part C product (2.63g, 5.72mmol) in MeOH (40ml) and THF (40ml) was treated with 4.0M sodium hydroxide (28ml, 112mmol) and heated at 80 deg.C for 48 h. The organic solvent was evaporated and the remaining aqueous solution was acidified with 1M HCl to yield a solid, which was collected by filtration, washed with water, and dried to give the target carboxylic acid (2.46g, 96%).

Part e. preparation of 2- (3, 5-diiodo-2-methoxyphenyl) -2-methylpropan-1-ol.

A solution of the product of part D (1.00g, 2.242mmol) in THF (40ml) was treated dropwise with borane THF complex 1.0M (20ml, 20mmol) and then heated at 50 ℃ for 24 h. The mixture was treated with methanol (20mL), refluxed for 30min, and concentrated. The resulting residue was washed with water, 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 (810mg, 84%).

Part f. preparation of tert-butyl (2- (3, 5-diiodo-2-methoxyphenyl) -2-methylpropoxy) -dimethylsilane.

A solution of the product of part E (432mg, 1.000mmol) in DMF (5ml) was treated with tert-butyldimethylsilyl chloride (301mg, 2.000mmol) and imidazole (204mg, 3.00mmol) and stirred for 2 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with hexane/EtOAc (9: 1) to give the desired product (522mg, 96%).

Part g. preparation of 1- (3- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a 50mL round bottom flask was added part F of the product (520mg, 0.952mmol), pyrimidine-2, 4(1H, 3H) -dione (117mg, 1.047mmol), N- (2-cyanophenyl) picolinamide (42.5mg, 0.190mmol), copper (I) iodide (18.13mg, 0.095mmol) and potassium phosphate (424mg, 1.999mmol) in DMSO (5 mL). The vessel was sealed, sparged with nitrogen and then heated at 60 ℃ for 24 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 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 gel, eluting with hexane/EtOAc (3: 2) to give the product as a solid (285mg, 65%).

Preparation of N- (6- (3- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

A5 mL microwave tube was charged with a solution of the product of part G (50mg, 0.094mmol), the product of example 2A, part B (32.7mg, 0.094mmol), potassium phosphate (42.0mg, 0.198mmol), PA-Ph (CAS 97739-46-3) (0.827mg, 2.83. mu. mol), and tris (dibenzylideneacetone) palladium (0) (0.863mg, 0.943. mu. mol) in THF (3.0mL) and water (1.0 mL). The vessel was sealed and the mixture sparged with nitrogen for 5min, then heated at 50 ℃ for 2 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 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 gel, eluting with hexane/EtOAc (3: 7) to give a solid (32mg, 54%).

Preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan-2-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

A solution of the product of part H (31mg, 0.050mmol) in THF (2.0ml) was treated with 1M TBAF (0.3ml, 0.3mmol) in THF and stirred overnight. The mixture was partitioned with water and ethyl acetate. The organic layer was washed three times with brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using CH ₂Cl₂Eluted with 2% to 8% methanol to give a solid (21mg, 83%). Melting point: 256 at 257 ℃.¹H NMR(300MHz，DMSO-d₆)δppm1.35(s，6H)3.08(s，3H)3.23(s，3H)3.67(d，J＝4.78Hz，2H)4.72(t，J＝4.78Hz，1H)5.65(d，J＝8.09Hz，1H)7.36(m，3H)7.74(m，3H)7.98(m，3H)10.04(s，1H)11.41(s，1H)。MS(ESI+)m/z 527(M+NH4)⁺。

EXAMPLE 28 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (1-methoxy-2-methylpropan-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.66).

Part a. preparation of 1, 5-diiodo-2-methoxy-3- (1-methoxy-2-methylpropan-2-yl) benzene.

A25 mL round bottom flask was charged with the product of example 27, part E (259mg, 0.6mmol) and a solution of sodium hydride (28.8mg, 1.200mmol) in THF (5 mL). The mixture was stirred for 30min and iodomethane (0.045l, 0.720mmol) was added. The mixture was stirred for 16h and partitioned between ethyl acetate and 1 MHCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to give an oil (235mg, 88%).

Part b. preparation of 1- (3-iodo-4-methoxy-5- (1-methoxy-2-methylpropan-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A25 mL round bottom flask was charged with part A of the product (230mg, 0.516mmol), pyrimidine-2, 4(1H, 3H) -dione (63.6mg, 0.567mmol), N- (2-cyanophenyl) picolinamide (23.02mg, 0.103mmol), copper (I) iodide (9.82mg, 0.052mmol), and potassium phosphate (230mg, 1.083mmol) in DMSO (5 mL). The vessel was sealed, sparged with nitrogen and heated at 60 ℃ for 16 h. The mixture was cooled and partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using CH ₂Cl₂Eluted with 2-5% methanol to give a solid (140mg, 63%).

Part c. preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (1-methoxy-2-methylpropan-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide.

A5 ml microwave tube was charged with the product of part B (43mg, 0.100mmol), the product of example 2A, part B (34.7mg, 0.100mmol), potassium phosphate (44.6mg, 0.210mmol), PA-Ph (CAS 97739-46-3) (0.876mg, 3.00. mu. mol) and tris (dibenzylideneacetone) palladium (0) (0.915mg, 0.999. mu. mol) in THF (3.0ml) and water (1.0 ml). The vessel was sealed, sparged with nitrogen for 5min and heated at 50 ℃ for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue is taken up in methanol/CH₂Cl₂Trituration (1: 1) gave a solid (28mg, 54%).¹H NMR(300MHz，DMSO-d₆)δppm 1.39(s，6H)3.08(s，3H)3.23(s，3H)3.25(s，3H)3.61(s，2H)5.65(d，J＝7.72Hz，1H)7.27(d，J＝2.57Hz，1H)7.37(d，J＝2.57Hz，1H)7.42(dd，J＝8.64，2.02Hz，1H)7.69(dd，J＝8.46，1.84Hz，1H)7.73(d，J＝2.21Hz，1H)7.78(d，J＝7.72Hz，1H)7.95(t，J＝8.27Hz，2H)8.02(s，1H)10.04(s，1H)11.41(s，1H)。MS(ESI+)m/z 541(M+NH4)⁺。

EXAMPLE 29 preparation of methyl 2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) -2-methylpropionate (compound IB-L0-2.70).

Part a. preparation of methyl 2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxyphenyl) -2-methylpropionate.

A100 mL round bottom flask was charged with the product of example 27, part C (410mg, 0.891mmol), 1H-pyrimidine-2, 4-dione (120mg, 1.069mmol) and a solution of tripotassium phosphate (397mg, 1.872mmol) in DMSO (5mL) under nitrogen to give a colorless suspension. N- (2-cyanophenyl) picolinamide (39.8mg, 0.178mmol) was added and the mixture sparged with nitrogen for 5 min. Copper (I) iodide (16.97mg, 0.089mmol) was added and the mixture was sparged again for 10min, placed under nitrogen and heated at 60 ℃ for 18 h. The mixture was cooled, partitioned between EtOAc and water, and pH adjusted to 1 with HCl. The aqueous layer was extracted with 2 × EtOAc. Combining the organic substances, adding water and saturated NaHCO₃And a saturated NaCl wash. Drying the organic layer (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The crude product was purified by chromatography on an ISCO 40g silica gel column using CH₂Cl₂Eluted with 3% MeOH to give a white foam (269mg, 68%).

Part b. preparation of methyl 2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) -2-methylpropionate.

A20 mL microwave tube was charged with the product of part A (0.444g, 1.0mmol), the product of example 2A, part B (0.365g, 1.050mmol) and a 3: 1 tetrahydrofuran-water (12mL) solution of tripotassium phosphate (0.446g, 2.100mmol) and degassed by nitrogen sparging for 20 min. The solution was then treated with PA-Ph (CAS 97739-46-3) (8.77mg, 0.030mmol) and tris (dibenzylidene-acetone) palladium (0) (9.16mg, 10.00. mu. mol), and then degassed for an additional 5 min. The microwave tube was then sealed, heated at 50 ℃ for 18h, cooled, partitioned between EtOAc and water, and adjusted to pH 1 with 1M HCl. EtOAc layer with water, saturated NaHCO ₃And a saturated NaCl wash. The organic layer was dried over sodium sulfate, stirred with 3-mercaptopropyl-functionalized silica gel for 1h, filtered, and concentrated. The crude product was purified by chromatography on an ISCO 12g silica gel column using CH₂Cl₂1-3% MeOH in to give light brown crystals (480mg, 98%).¹H NMR(300MHz，DMSO-d₆)δppm1.52(s，6H)3.08(s，3H)3.14(s，3H)3.64(s，3H)5.67(dd，J＝8.09，1.84Hz，1H)7.37-7.48(m，3H)7.65(dd，J＝8.46，1.84Hz，1H)7.73(d， J＝2.21Hz，1H)7.83(d，J＝8.09Hz，1H)7.96(dd，J＝8.64，5.70Hz，2H)8.01(s，1H)10.05(s，1H)11.45(s，1H)。MS(ESI-)m/z 536(M-H)⁺。

EXAMPLE 30 preparation of 2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) -2-methylpropionic acid (compound IB-L0-2.77).

The product from example 29 (108mg, 0.2mmol) and sodium hydroxide (1mL, 4.00mmol) in methanol, THF, water(3: 1, 10mL) the mixture was heated at 80 ℃ for 18h, cooled, and carefully acidified to pH 1 with concentrated HCl to form a white precipitate. The solid was collected by filtration, washed with water and dried. The crude material was triturated in 1mL 1: 1EtOAc/MeOH, sonicated for 5min, and the solid collected by filtration as a light white solid (58mg, 54% yield), mp > 300 ℃.¹H NMR(300MHz，DMSO-d₆)δppm 1.50(s，6H)3.08(s，3H)3.18(s，3H)5.66(d，J＝7.72Hz，1H)7.34-7.45(m，3H)7.67(dd，J＝8.64，1.65Hz，1H)7.73(d，J＝1.84Hz，1H)7.82(d，J＝7.72Hz，1H)7.96(dd，J＝9.01，4.60Hz，2H)8.02(s，1H)10.04(s，1H)11.43(s，1H)12.15(s，1H)。MS(ESI-)m/z522(M-H)⁺。

EXAMPLE 31 preparation of methyl 5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) benzoate (Compound IB-L0-2.72).

Part a. preparation of methyl 3, 5-diiodo-2-methoxybenzoate.

A mixture of 2-hydroxy-3, 5-diiodobenzoic acid (3.9g, 10.0mmol), potassium carbonate (4.15g, 30.0mmol) and methyl dithioate (2.77g, 22.0mmol) in acetone (33ml) was heated under reflux for 16h, cooled and concentrated. The residue was dissolved in EtOAc, washed with water, brine and dried (Na) ₂SO₄) Filtered and concentrated to give an off-white solid (4.2g, quantitative yield).

Part b. preparation of methyl 5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxybenzoate.

A100 mL round bottom flask was charged with the product of part A (2.09g, 5.0mmol), 1H-pyrimidine-2, 4-dione (0.67g, 6.0mmol) and a solution of tripotassium phosphate (2.2g, 10.5mmol) in DMSO (20mL) under nitrogen to give a colorless suspensionAnd (4) floating liquid. N- (2-cyanophenyl) picolinamide (220mg, 1.0mmol) was added and the mixture sparged with nitrogen for 5 min. Copper (I) iodide (95mg, 0.5mmol) was added and the mixture was again sparged for 10min, placed under nitrogen and heated at 60 ℃ for 18 h. The mixture was cooled, partitioned between EtOAc and water, and pH adjusted to 1 with HCl. The aqueous layer was extracted with 2 × EtOAc. Combining the organic substances, adding water and saturated NaHCO₃And a saturated NaCl wash. Drying the organic layer (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The crude product was purified by chromatography on an ISCO 40g silica gel column using CH₂Cl₂Eluted with 3% MeOH to give a white foam (1.0g, 50%).

Part c. preparation of methyl 5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) benzoate.

A mixture of the product of part B (101mg, 0.25mmol), the product of example 2A, part B (91mg, 0.263mmol) and tripotassium phosphate (111mg, 0.525mmol) in 3: 1 tetrahydrofuran-water (12mL) was degassed by nitrogen sparge for 20 min. The solution was then treated with PA-Ph (CAS97739-46-3) (2.192mg, 7.50. mu. mol) and tris (dibenzylideneacetone) palladium (0) (2.289mg, 2.500. mu. mol), and then degassed for an additional 5 min. The microwave tube was then sealed, heated at 50 ℃ for 18h, cooled, partitioned between EtOAc and water, and adjusted to pH 1 with 1M HCl. EtOAc layer with water, saturated NaHCO₃And a saturated NaCl wash. Dry organic layer Na₂SO₄Stirred with 3-mercaptopropyl-functionalized silica gel for 1h, filtered and concentrated. The crude product was purified by chromatography on an ISCO 12g silica gel column using CH₂Cl₂Eluted with 3% MeOH to give an off-white foam (80mg, 63%).¹H NMR(300MHz，DMSO-d₆)δppm 3.09(s，3H)3.45(s，3H)3.89(s，3H)5.69(d，J＝7.72Hz，1H)7.43(dd，J＝8.82，2.21Hz，1H)7.68-7.79(m，4H)7.84(d，J＝7.72Hz，1H)7.89-8.01(m，2H)8.09(s，1H)10.06(s，1H)11.49(s，1H)。MS(ESI-)m/z494(M-H)⁺。

EXAMPLE 32 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.57).

Part a. preparation of 1, 3, 5-triiodo-2-methoxybenzene.

A250 mL pressurized vessel was charged with a solution of 2, 4, 6-triiodophenol (5g, 10.60mmol) in MTBE (60mL) to give a yellow solution. The solution was cooled in an ice bath and 2.0M trimethylsilyldiazomethane (7.95mL, 15.90mmol) was added dropwise rapidly followed by methanol (6mL) to allow the bubbles to settle. The vessel was sealed 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 NaHCO ₃And a saturated NaCl wash. Drying EtOAc (MgSO)₄) Filtered and concentrated to give a brown solid which was used without purification (4.8g, 94%).

Part b. preparation of 1- (3, 5-diiodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

A100 mL round bottom flask was charged with the product of part A (3.5g, 7.2mmol), 1H-pyrimidine-2, 4-dione (0.97g, 8.64mmol), and a solution of tripotassium phosphate (3.2g, 15.0mmol) in DMSO (50mL) under nitrogen to give a colorless suspension. N- (2-cyanophenyl) picolinamide (320mg, 1.44mmol) was added and the mixture sparged with nitrogen for 5 min. Copper (I) iodide (137mg, 0.72mmol) was added and the mixture was again sparged for 10min, placed under nitrogen and heated at 60 ℃ for 18 h. The mixture was cooled, partitioned between EtOAc and water, and pH adjusted to 1 with HCl. The aqueous layer was extracted with 2 × EtOAc. Combining the organic substances, adding water and saturated NaHCO₃And saturated NaCl, dried (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The resulting solid was triturated in 2: 1 hexanes/EtOAc to give an off-white powder (2.2g, 62%).

Part c. preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

The product of part B, 1- (3, 5-diiodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione (118mg, 0.25mmol), the product of example 2A, part B (87mg, 0.25mmol), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride (II) CH₂Cl₂A mixture of complex (10.21mg, 0.013mmol) and sodium carbonate (0.250ml, 0.25mmol) in toluene (1.0ml) and ethanol (1.0ml) was sparged with nitrogen for 5min and microwaved at 100 ℃ for 30 min. The mixture was cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane (2: 3-4: 1) to give the title compound (16mg, 11%).¹H NMR(300MHz，DMSO-d₆)δppm 3.08(s，3H)3.35(s，3H)5.67(d，J＝8.09Hz，1H)7.42(dd，J＝8.82，2.21Hz，1H)7.59(d，J＝2.57Hz，1H)7.73(m，2H)7.81(d，J＝8.09Hz，1H)7.95(m，3H)8.09(s，1H)10.06(s，1H)11.47(s，1H)。MS(ESI-)m/z 562(M-H)⁺。

EXAMPLE 33 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- ((trimethylsilyl) ethynyl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.78).

Ethynyltrimethylsilane (0.044mL, 0.32mmol), the product of example 32 (45.1mg, 0.08mmol), copper (I) iodide (0.762mg, 4.0. mu. mol), bis (triphenyl-phosphine) palladium (II) chloride (2.81mg, 4.0. mu. mol) and triethylamine (0.056mL, 0.40mmol) in acetonitrile (2mL) were mixed in a 5mL microwave tube. The mixture was sparged with nitrogen for 5min, sealed and heated at 80 ℃ for 20min with microwave. Cooling the reaction mixture with Ethyl acetate and water partition. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using CH₂Cl₂1-4% methanol to give a solid (18mg, 42%) m.p.175-178 ℃.¹H NMR(300MHz，DMSO-d₆)δppm 0.25(s，9H)3.07(s，3H)3.65(s，3H)5.66(dd，J＝7.91，2.02Hz，1H)7.41(dd，J＝8.82，2.21Hz，1H)7.58(m，2H)7.69(dd，J＝8.46，1.84Hz，1H)7.72(d，J＝2.21Hz，1H)7.81(d，J＝7.72Hz，1H)7.93(m，2H)8.05(d，J＝1.32Hz，1H)10.04(s，1H)11.45(d，J＝2.21Hz，1H)。MS(ESI+)m/z 534(M+H)⁺。

EXAMPLE 34 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (methylsulfonyl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.68).

Part a. preparation of 4-nitrobenzene-2-diazo-1-oxide.

A250 mL round bottom flask was charged with a 48% solution of 2-amino-4-nitrophenol (6.165g, 40.0mmol) in tetrafluoroboric acid (15 mL). A solution of sodium nitrite (2.76g, 40.0mmol) in water (6ml) was added dropwise at 0 ℃ and the mixture was stirred at room temperature for 30 min. The solid was collected by filtration and washed with tetrafluoroboric acid and water. The solid was suspended in acetone (50mL), filtered and dried to give a solid (3.31g, 50%).

Part b. preparation of 2- (methylthio) -4-nitrophenol.

A solution of the product of part A (2.70g, 16.35mmol) in ice water (250g) was added to a 1L beaker to give a brown suspension. Copper (0.520g, 8.18mmol) was added followed by the slow addition of a solution of sodium thiomethoxide (2.292g, 32.7mmol) 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 to produce a solid which was collected by filtration and dried (2.53g, 84%).

Part c. preparation of 2- (methylsulfonyl) -4-nitrophenol.

A250 mL round bottom flask was charged with a solution of part B product (1.111g, 6.00mmol) in MeOH (20mL) to give a brown suspension. A solution of oxone (7.746g, 12.60mmol) in water (20ml) was added slowly at 0 ℃. The mixture was warmed to room temperature, stirred for 1h, and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using CH₂Cl₂1% to 5% methanol in (1%) to give a solid (0.472g, 36%).

Part d. preparation of 2-iodo-6- (methylsulfonyl) -4-nitrophenol.

A50 mL round bottom flask was charged with a solution of part C product (470mg, 2.164mmol) in MeOH (10mL) and water (2.5 mL). Iodine monochloride (0.130ml, 2.60mmol) in CH is added dropwise₂Cl₂(2.0mL), the mixture was stirred at room temperature, poured into water (200mL) and stirred for 10 min. The resulting solid was collected by filtration and dried (636mg, 86%).

Part e. preparation of 1-iodo-2-methoxy-3- (methylsulfonyl) -5-nitrobenzene.

To a 50mL pressurized vessel was added a solution of the product of part D (630mg, 1.836mmol) in MTBE (6mL) to give a yellow solution. The mixture was cooled in an ice bath and 2M trimethylsilyl-diazomethane (1.377mL, 2.75mmol) was added dropwise rapidly followed by MeOH (0.4mL) to allow the bubbles to settle. The vessel was sealed 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, brine, dried over sodium sulfate, filtered and evaporated to give an off-white solid (655mg, 100%).

Part f. preparation of 3-iodo-4-methoxy-5- (methylsulfonyl) aniline.

A250 mL round bottom flask was charged with part E of the product (0.650g, 1.820mmol), ammonium chloride (0.146g, 2.73mmol) and iron (0.508g, 9.10mmol) in THF/MeOH/water (50mL, 2/2/1). The mixture was refluxed for 2h, 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 (590mg, 99%).

Preparation of (E) -N- (3-iodo-4-methoxy-5- (methylsulfonyl) phenylcarbamoyl) -3-methoxyacrylamide.

A100 mL round bottom flask was charged with a solution of part F (500mg, 1.528mmol) in DMF (15.0 mL). The solution was cooled to-20 ℃ under nitrogen and (E) -3-methoxyacryloyl isocyanate (15.28ml, 6.11 mmol; prepared according to Santana, L. et al, J.Heterococcus chem.1999, 36, 293-295) was added dropwise. The mixture was stirred at this temperature for 15min, then warmed to room temperature and stirred for 45 min. The mixture was diluted with ethyl acetate, washed with water (3X 50mL), brine (3X 50mL), dried over sodium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate/hexanes to give a solid (425mg, 61%).

Part H. preparation of 1- (3-iodo-4-methoxy-5- (methylsulfonyl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A100 mL round bottom flask was charged with a solution of part G of the product (420mg, 0.925mmol) in ethanol (10mL) to give a suspension. A solution of concentrated sulfuric acid (1mL, 18.76mmol) in water (10mL) was added and the mixture was heated at 110 ℃ for 2 h. The reaction mixture was cooled, diluted with water (50ml) and stirred for 10 min. The solid material was collected by filtration, washed with water, and dried to give a white solid (325mg, 83%).

Preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (methylsulfonyl) phenyl) naphthalen-2-yl) methanesulfonamide.

To a 5mL microwave tube was added the product of part H (63.3mg, 0.15mmol), the product of example 2A, part B (52.1mg, 0.150mmol), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride complex (6.12mg, 7.50. mu. mol), anda solution of 1M sodium carbonate (0.150ml, 0.150mmol) in a solvent of toluene (1.0ml) and ethanol (1.0 ml). The vessel was sealed and the mixture sparged with nitrogen for 5min and microwaved at 100 ℃ for 30 min. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel using CH ₂Cl₂Eluting with 1-8% methanol to obtain crude product. Final trituration in 1: 1 methanol/ethyl acetate afforded a pure solid (26mg, 34%).¹H NMR(300MHz，DMSO-d₆)δppm 3.10(s，3H)3.44(s，3H)3.45(s，3H)5.71(d，J＝8.09Hz，1H)7.44(dd，J＝8.82，2.21Hz，1H)7.75(d，J＝1.84Hz，1H)7.80(dd，J＝8.46，1.84Hz，1H)7.86(d，J＝8.09Hz，1H)7.91(d，J＝2.57Hz，1H)7.96(d，J＝2.57Hz，1H)8.00(m，2H)8.16(d，J＝1.47Hz，1H)10.10(s，1H)11.51(s，1H)。MS(ESI+)m/z 533(M+NH4)⁺。

EXAMPLE 35 preparation of N- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) methanesulfonamide (compound IB-L0-2.75).

Part a. preparation of 2, 4-diiodo-6-nitrophenol.

To a solution of 2-nitrophenol (2.78g, 20mmol) in MeOH (120mL) and water (30mL) was added dropwise iodine monochloride (2.105mL, 42.0mmol) in 10mL CH₂Cl₂And (3) solution. The mixture was stirred for 2h, poured into 600mL of water, stirred and sonicated for 30 min. The mixture was filtered and a yellow solid was collected, washed with 3 × water (50 mL each) and dried to constant weight (7.3g, 93%).

Part b. preparation of 1, 5-diiodo-2-methoxy-3-nitrobenzene.

To a 50mL pressurized vessel were added part A of the product and MTBE (10mL) to give a yellow solution. The solution was cooled in an ice bath and 2M trimethylsilyldiazomethane (2.251mL, 4.50mmol) was added dropwise rapidly followed by MeOH (0.6mL) to allow the bubbles to settle. The vessel was sealed and allowed to warm to room temperature for 4h with stirring. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid (1.22g, 100%).

Part c. preparation of 3, 5-diiodo-2-methoxyaniline.

A250 round bottom flask was charged with the product of part B (0.98g, 2.420mmol), ammonium chloride (0.194g, 3.63mmol) and iron (0.676g, 12.10mmol) in THF/methanol/water (20 mL/10 mL). The mixture was refluxed for 16h, cooled and filtered. The filtrate was evaporated and the residue was partitioned with water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil (780mg, 86%).

Part d. preparation of 1- (3-amino-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

A25 mL round-bottom flask was charged with part C of the product (650mg, 1.734mmol), pyrimidine-2, 4(1H, 3H) -dione (214mg, 1.907mmol), N- (2-cyanophenyl) picolinamide (77mg, 0.347mmol), copper (I) iodide (33.0mg, 0.173mmol) and potassium phosphate (773mg, 3.64mmol) in DMSO (5 mL). The vessel was sealed and the mixture was sparged with nitrogen for 15min and heated at 60 ℃ for 16 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue is chromatographed on silica gel using 5: 95 methanol/DCH ₂Cl₂CM eluted to give a solid (125mg, 20%).

Part e. preparation of N- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxy-phenyl) methanesulfonamide.

Treatment of the product of fraction D with methanesulfonyl chloride (0.048ml, 0.612mmol)A solution of substance (110mg, 0.306mmol) in pyridine (2ml) was stirred for 24 h. The solvent was evaporated and the residue partitioned with ethyl acetate and 1M HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel using CH₂Cl₂Eluted with 2-5% methanol to obtain solid (20mg, 15%).

Part f. preparation of N- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) methanesulfonamide.

To a 5mL microwave tube was added the product of part E (18mg, 0.041mmol), the product of example 2A, part B (14.30mg, 0.041mmol), potassium phosphate (18.35mg, 0.086mmol), PA-Ph (CAS 97739-46-3) (0.361mg, 1.235. mu. mol), and tris (dibenzylideneacetone) dipalladium (0) (0.377mg, 0.412. mu. mol) in THF (3.0mL) and water (1.0 mL). The vessel was sealed and the mixture was sparged with nitrogen for 5min and heated at 50 ℃ for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel using CH ₂Cl₂Eluting with 2-5% methanol to obtain solid. At 1: 1 methanol/CH₂Cl₂Final trituration in (g) gave the desired product (7mg, 32%).¹H NMR(300MHz，DMSO-d₆)δppm 3.09(s，3H)3.17(s，3H)3.37(s，3H)5.69(dd，J＝7.91，2.02Hz，1H)7.34(d，J＝2.57Hz，1H)7.43(dd，J＝8.82，2.21Hz，1H)7.47(d，J＝2.57Hz，1H)7.73(m，2H)7.81(d，J＝8.09Hz，1H)7.94(d，J＝6.25Hz，1H)7.97(d，J＝6.62Hz，1H)8.07(s，1H)9.45(s，1H)10.05(s，1H)11.45(d，J＝1.84Hz，1H)。MS(ESI-)m/z 529(M-H)。

EXAMPLE 36 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (trifluoromethyl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.56).

Part a. preparation of 4-iodo-2- (trifluoromethyl) phenol.

To a solution of 2- (trifluoromethyl) phenol (3.24g, 20mmol) in MeOH (40ml) was added sodium hydroxide (0.960g, 24.0mmol) and stirred until the hydroxide dissolved. The mixture was cooled to 0 deg.C, sodium iodide (3.0g, 20mmol) was added, and then a 10% aqueous sodium hypochlorite solution (9.0ml, 14.6mmol) was added dropwise. Sodium iodide was added, followed by sodium hypochlorite, and this was repeated twice more. The mixture was stirred at ambient temperature for 2h and treated with dropwise concentrated HCl to pH 1. The mixture was extracted with 3 × EtOAc. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel eluting with EtOAc/hexanes (1: 9) to give the mono-iodo product (5.0g, 87%).

Part b. preparation of 2-bromo-4-iodo-6- (trifluoromethyl) phenol.

A250 mL round bottom flask was charged with the product of part A (5.00g, 17.36mmol) and 1, 3-dibromo-5-dimethylhydantoin (2.73g, 9.55mmol) in CHCl ₃(80mL) to give an orange solution. The mixture was stirred for 2h, washed with water, brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel, eluting with ethyl acetate/hexane (5: 95) to give a solid (3.5g, 54%).

Part c. preparation of 1-bromo-5-iodo-2-methoxy-3- (trifluoromethyl) benzene.

A mixture of the product of part B (3.2g, 8.72mmol), methyl iodide (1.36ml, 21.8mmol) and 50% sodium hydroxide (0.507ml, 9.59mmol) in acetone (20ml) was stirred for 24 h. The solvent 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. The crude material was purified on silica gel, eluting with ethyl acetate/hexane (5: 95) to give a solid (2.67g, 80%).

Part d. preparation of 1- (3-bromo-4-methoxy-5- (trifluoromethyl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a 20mL microwave tube was added a solution of the product of part C (762mg, 2.0mmol), pyrimidine-2, 4(1H, 3H) -dione (247mg, 2.2mmol), N- (2-cyanophenyl) picolinamide (89mg, 0.4mmol), copper (I) iodide (38.1mg, 0.2mmol) and potassium phosphate (892mg, 4.2mmol) in DMSO (10 mL). The vessel was sealed and the mixture was sparged with nitrogen for 15min and heated at 60 ℃ for 16 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified on silica gel, eluting with ethyl acetate/hexane (2: 3), to give the desired product (63mg, 9%).

Part e. preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (trifluoromethyl) phenyl) naphthalen-2-yl) methanesulfonamide.

A5 mL microwave tube was charged with the product of part D (60mg, 0.164mmol), the product of example 2A, part B (62.8mg, 0.181mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (5.36mg, 8.22. mu. mol) and potassium phosphate (69.8mg, 0.329mmol) in THF/water (3mL/1 mL). The vessel was sealed and the mixture was sparged with nitrogen for 5min and heated at 60 ℃ for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified by reverse phase chromatography to give the title compound as a solid (26mg, 31%).¹H NMR(300MHz，DMSO-d₆)δppm 3.10(s，3H)3.37(s，3H)5.71(dd，J＝7.72，2.21Hz，1H)7.44(dd，J＝8.82，2.21Hz，1H)7.75(s，1H)7.78(d，J＝1.84Hz，1H)7.88(m，3H)7.98(d，J＝3.31Hz，1H)8.01(d，J＝3.68Hz，1H)8.15(s，1H)10.09(s，1H)11.51(d，J＝2.21Hz，1H)。MS(ESI-)m/z 504.1(M-H)⁺。

EXAMPLE 37 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (perfluoroethyl) phenyl) naphthalen-2-yl) methanesulfonamide (compound IB-L0-2.60).

Part a. preparation of 1-methoxy-4-nitro-2- (perfluoroethyl) benzene.

To a 250mL round bottom flask was added a solution of 2-bromo-1-methoxy-4-nitrobenzene (3.5g, 15.08mmol), copper (I) iodide (5.75g, 30.2mmol) and sodium 2, 2, 3, 3, 3-pentafluoropropionate (5.25g, 28.2mmol) in DMF (75mL) and toluene (25mL) to give a brown suspension. The mixture was heated at 150 ℃ and toluene was removed by a Dean-Stark separator. The mixture was heated at 155 ℃ for 6h under nitrogen, cooled, poured into 100mL of water and 100mL of ether, filtered through a 1 inch plug of Celite, and the plug rinsed with ether. The filtrate layer was separated. The organic layer was washed with brine and dried (Na) ₂SO₄) Filtering, and concentrating. The dark oil was flash chromatographed on an Isco 40g silica gel column, eluting with 4: 1 hexane/EtOAc to give a yellow oil which is a (3: 1) mixture of the title material and starting material (1.5g, 37%).

Part b. preparation of 4-nitro-2- (perfluoroethyl) phenol.

A100 mL round bottom flask was charged with the product of part A (1.4g, 5.16mmol) and pyridine hydrochloride (4g, 34.6 mmol). The mixture was heated at 210 ℃ for 20min, cooled and partitioned between EtOAc and water. The organic layer was washed with brine and dried (Na)₂SO₄) And (4) concentrating. The crude product was flash chromatographed on an Isco12g silica gel column, eluting with 3: 2 hexanes/EtOAc to give a yellow oil (1.3g, 98%).

Part c. preparation of 2-iodo-4-nitro-6- (perfluoroethyl) phenol.

A100 mL round bottom flask was charged with the product of part B (1.3g, 5.06mmol) and a solution of N-iodosuccinimide (1.251g, 5.56mmol) in acetonitrile (16.85mL) to give a yellow solution. The solution was stirred for 16h, 100mLEtOAc dilution, washing with 2X 50ml 10% sodium thiosulfate, brine, and drying (Na)₂SO₄) Concentrated to an orange semi-solid. The semi-solid was flash chromatographed on an Isco 40g silica gel column, eluting with 3: 1 hexanes EtOAc to give a dark yellow/orange oil (1.3g, 67%).

Part d. preparation of 1-iodo-2-methoxy-5-nitro-3- (perfluoroethyl) benzene.

A100 mL round bottom flask was charged with a solution of part C product (1.04g, 2.72mmol), potassium carbonate (0.563g, 4.07mmol), and methyl dithioate (0.411g, 3.26mmol) in acetone (20mL) to give a brown suspension. The mixture was heated at gentle reflux for 16h, cooled, diluted into EtOAc, washed with water and brine. Drying the organic layer (Na)₂SO₄) Filtered and concentrated to a yellow oil, which was purified by flash chromatography on an Isco 40g silica gel column eluted with 9: 1 hexanes/EtOAc (600mg, 56%).

Part e. preparation of 3-iodo-4-methoxy-5- (perfluoroethyl) aniline.

A250 mL round bottom flask was charged with a solution of part D product (0.6g, 1.511mmol), iron (0.422g, 7.56mmol) and ammonium chloride (0.121g, 2.267mmol) in a mixed solvent of EtOH (9mL), THF (9mL) and water (3mL) to give a brown suspension which was heated at 95-100 deg.C for 2 h. The reaction mixture was filtered through a plug of Celite, which was repeatedly rinsed with EtOH. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with water, brine and dried (Na)₂SO₄) Filtered and concentrated to give an oil (560mg, 99%).

Part f. preparation of 1, 5-diiodo-2-methoxy-3- (perfluoroethyl) benzene.

A25 mL round bottom flask was charged with a solution of part E of the product (0.565g, 1.539mmol), tert-butyl nitrite (0.293mL, 2.463mmol), copper (I) iodide (0.293g, 1.539mmol), sodium iodide (0.231g, 1.539mmol) and iodine (0.195g, 0.770mmol) in DME (15.39mL) under nitrogen to give a brown suspension. The mixture was heated at 60 ℃ for 3h, cooled, filtered through Celite, and the Celite pad was washed well with EtOAc. EtOAc filterThe solution was treated with 10% sodium thiosulfate, brine and dried (Na)₂SO₄) Filtered and concentrated to a dark oil. The crude material was purified by flash chromatography on an Isco 40g silica gel column, eluting with 95: 5 hexanes/EtOAc to give a yellow oil (360mg, 49%).

Part g. preparation of 1- (3-iodo-4-methoxy-5- (perfluoroethyl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

A20 mL microwave tube was charged with a solution of the product of part F (0.36g, 0.753mmol), 1H-pyrimidine-2, 4-dione (0.101g, 0.904mmol), tripotassium phosphate (0.336g, 1.582mmol), N- (2-cyanophenyl) picolinamide (0.034g, 0.151mmol), and copper (I) iodide (0.014g, 0.075mmol) in DMSO (7 mL). The vessel was sealed and the mixture was sparged with nitrogen for 30min, heated at 60 ℃ for 24h, cooled and diluted into EtOAc. EtOAc layer with 1M HCl, saturated NaHCO ₃And saturated NaCl, dried (Na)₂SO₄) Filtering, and concentrating. The residue was flash chromatographed on an Isco 40g silica gel column, eluting with hexane- - > 1: 1 hexane/EtOAc to give a yellow foam (100mg, 29%).

Part H. preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (perfluoroethyl) phenyl) naphthalen-2-yl) methanesulfonamide.

A mixture of the product of part G (0.10G, 0.216mmol), the product of example 2A, part B (0.075G, 0.216mmol) and a solution of tripotassium phosphate (0.096G, 0.454mmol) in 3: 1 tetrahydrofuran-water (5mL) was mixed in a 5mL microwave tube and degassed by nitrogen sparging for 10 min. Then, it was treated with a mixture of PA-Ph (CAS 97739-46-3) (1.898mg, 6.49. mu. mol) and tris (dibenzylideneacetone) dipalladium (0) (1.982mg, 2.164. mu. mol), followed by degassing for a further 5 min. The flask was then sealed and stirred at 50 ℃ for 16h and partitioned between EtOAc and water. The EtOAc layer was washed with 0.1M HCl, saturated NaHCO₃And a saturated NaCl wash. With Na₂SO₄The organics were dried, stirred with 3-mercapto-propyl functionalized silica for 0.5h, metals removed, filtered and concentrated. The crude product was purified by chromatography on an ISCO 12g silica gel column using CH₂Cl₂--＞CH₂Cl₂Eluted with 3% MeOH to give a pale yellow foam (84mg, 99%) m.p.162-165 ℃. ¹H NMR(300MHz，DMSO-d₆)δppm 3.10(s，3H)3.33(s，3H)5.70(d，J＝7.72Hz，1H)7.44(dd，J＝8.82，2.21Hz，1H)7.70-7.76(m，2H)7.80(d，J＝2.57Hz，1H)7.86(d，J＝8.09Hz，1H)7.91(d，J＝2.57Hz，1H)8.00(dd，J＝8.82，2.94Hz，2H)8.12(s，1H)10.10(s，1H)11.50(s，1H)。MS(ESI-)m/z 554(M-H)⁺。

EXAMPLE 38 preparation of (E) -N' - (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide (compound IB-L0-2.51).

Part a. preparation of 1- (3-bromo-4-methoxy-5- (1-oxo-2, 3-dihydro-1H-inden-5-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione.

A100 mL round bottom flask was charged with the product of example 18, part C (846mg, 2.00mmol), the product of example 4, part A (516mg, 2.000mmol), potassium phosphate (892mg, 4.20mmol), PA-Ph (CAS 97739-46-3) (17.54mg, 0.060mmol), and tris (dibenzylideneacetone) -dipalladium (0) (18.31mg, 0.020mmol) in THF (12.0mL) and water (4.0 mL). The vessel was sealed and the mixture sparged with nitrogen for 5min and stirred at ambient temperature for 72 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered through Celite and evaporated. The residue was purified on silica gel using CH₂Cl₂1-4% methanol in (1-4%) to give a solid (690mg, 81%).

Part b. preparation of (E) -N' - (5- (3-bromo-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide.

A50 mL round bottom flask was charged with the product of part A (685mg, 1.603mmol) and a solution of methanesulfonyl hydrazide (194mg, 1.764mmol) in MeOH (20 mL). The mixture was warmed to 40 ℃ and stirred for 24 h. The mixture was cooled, filtered and washed with methanol to give a solid (569mg, 68%).

Part c. preparation of (E) -N' - (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide.

A5 mL microwave tube was charged with a solution of the product of part B (52mg, 0.100mmol), thiophen-2-ylboronic acid (12.81mg, 0.100mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (3.26mg, 5.01. mu. mol), and potassium phosphate (42.5mg, 0.200mmol) in THF (3.0mL) and water (1.0 mL). The mixture was sparged with nitrogen for 5min and heated at 50 ℃ for 3 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over 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 AA to give a white solid (27mg, 52%).¹H NMR(300MHz，DMSO-d₆)δppm 2.86(m，2H)3.09(s，3H)3.14(m，2H)3.32(s，3H)5.69(d，J＝7.72Hz，1H)7.18(dd，J＝5.15，3.68Hz，1H)7.41(d，J＝2.57Hz，1H)7.63(m，3H)7.75(m，2H)7.86(d，J＝8.09Hz，1H)7.91(d，J＝2.94Hz，1H)9.96(s，1H)11.48(s，1H)。MS(ESI+)m/z 523(M+H)⁺。

EXAMPLE 39 preparation of (E) -N' - (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) -2, 3-dihydro-1H-indene-1-ylidene) methanesulfonyl hydrazide (compound IB-L0-2.55).

A5 mL microwave tube was charged with a solution of the product of example 38, part B (52mg, 0.100mmol), furan-2-ylboronic acid (11.20mg, 0.100mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (3.26mg, 5.01. mu. mol), and potassium phosphate (42.5mg, 0.200mmol) in THF (3.0mL) and water (1.0 mL). The mixture was sparged with nitrogen for 5min and heated at 50 ℃ for 3 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over 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 AA to give a solid (24mg, 47%).¹H NMR(300MHz，DMSO-d₆)δppm 2.86(m，2H)3.09(s，3H)3.14(m，2H)3.36(s，3H)5.68(d，J＝8.09Hz，1H)6.69(dd，J＝3.31，1.84Hz，1H)7.09(d，J＝3.31Hz，1H)7.41(d，J＝2.57Hz，1H)7.62(m，2H)7.75(d，J＝8.09Hz，1H)7.80(d，J＝2.57Hz，1H)7.86(m，2H)9.97(s，1H)11.46(s，1H)。MS(ESI+)m/z507(M+H)⁺。

EXAMPLE 40 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-ethoxyphenyl) naphthalen-2-yl) methanesulfonamide (Compound IB-L0-2.23).

Part a. preparation of 2-tert-butyl-4-iodophenol.

To a 250mL round bottom flask was added a solution of 2-tert-butylphenol (3.76g, 25mmol) in MeOH (50.0mL) to give a colorless solution. Sodium hydroxide (1.200g, 30.0mmol) was added and the mixture stirred until the hydroxide was completely dissolved. The solution was cooled to 0 ℃ and treated with sodium iodide (1.75g, 11.6mmol) and then a 10% sodium hypochlorite solution (7.2ml, 11.6mmol) was added dropwise. Adding sodium iodide, then adding sodium hypochlorite, repeating twice, and stirring the mixture at 0 deg.C for 3 And 0 min. The mixture was treated with 10% w/w sodium thiosulfate solution, stirred for 30min, treated with dropwise concentrated HCl to a constant pH of 1. The mixture was extracted with 3 × EtOAc. The extracts were combined, washed with brine and dried (MgSO)₄) Filtering, and concentrating. The crude oil was flash chromatographed on an ISCO 80g silica gel column, eluting with hexane- - > 4: 1 hexane/EtOAc to give a yellow oil (5.2g, 75%).

Part b. preparation of 2-bromo-6-tert-butyl-4-iodophenol.

To a 250mL round bottom flask was added the product of part A (4.8g, 17.38mmol) and a solution of 1, 3-dibromo-5, 5-dimethylhydantoin (2.61g, 9.13mmol) in chloroform (87mL) to give an orange solution. The reaction mixture was stirred for 2h to give a black solution, washed with water, brine and dried (Na)₂SO₄) And (4) concentrating. The black oil was flash chromatographed on 120g Isco silica gel column, eluting with hexane, to give a pink solid (4.84g, 78%).

Part c. preparation of 1-bromo-3-tert-butyl-2-ethoxy-5-iodobenzene.

A50 mL round bottom flask was charged with the product of part B (888mg, 2.5mmol), iodoethane (409mg, 2.63mmol), and potassium carbonate (415mg, 3.00mmol) in acetone (12mL) to give a green suspension. The mixture was heated under reflux for 16h, cooled and concentrated. The residue was partitioned between water and EtOAc. The organic layer was washed twice with brine and Na ₂SO₄Dried, filtered and concentrated to a red oil. The oil was flash chromatographed on an Isco 40g silica gel column, eluting with hexane, to give a clear oil (820mg, 86%).

Part d. preparation of 1- (3-bromo-5-tert-butyl-4-ethoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

A solution of the product of part C (0.4g, 1.044mmol), 1H-pyrimidine-2, 4-dione (0.140g, 1.253mmol) and tripotassium phosphate (0.465g, 2.193mmol) in DMSO (5mL) was added to a 20mL microwave tube under a nitrogen flush to give a colorless suspension. N- (2-cyanophenyl) picolinamide (0.047g, 0.209mmol) was added and the mixture sparged with nitrogen for 10 min. AddingCopper (I) iodide (0.020g, 0.104mmol) was added and the mixture was again sparged for 10min, placed under nitrogen and heated at 60 ℃ for 18 h. The mixture was cooled, partitioned between EtOAc and water, and pH adjusted to 1 with HCl. The aqueous layer was extracted with 2 × EtOAc. Combining the organic substances, adding water and saturated NaHCO₃And a saturated NaCl wash. Drying the organic layer (Na)₂SO₄) Stirred with 3-mercaptopropyl-functionalized silica for 1h, filtered and concentrated. The crude product was purified by chromatography on an ISCO 12g silica gel column using CH₂Cl₂Eluted with 2% MeOH to give a white powder (266mg, 69%).

Part e. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-ethoxyphenyl) naphthalen-2-yl) methanesulfonamide.

A5 mL microwave tube was charged with the product of part D (55.1mg, 0.15mmol), the product of example 2A, part B (52.1mg, 0.150mmol), tripotassium phosphate (63.7mg, 0.300mmol) and a solution of 1, 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (4.89mg, 7.50. mu. mol) in THF (3mL) in water (1 mL). The mixture was sparged with nitrogen for 10min, sealed, heated at 50 ℃ for 4h, cooled, and diluted into EtOAc. EtOAc layer with 1M HCl, saturated NaHCO₃Washed with saturated NaCl and dried (Na)₂SO₄) Simultaneously, the mixture is treated by mercaptopropyl silica gel, filtered and concentrated. The residue is flash chromatographed on a 12g Isco silica gel column using CH₂Cl₂Eluted with 2% MeOH to give a solid, (16mg, 21%) m.p.196-202 ℃.¹H NMR(300MHz，DMSO-d₆)δppm 1.00(t，J＝6.99Hz，3H)1.44(s，9H)3.09(s，3H)3.43(q，J＝7.11Hz，2H)5.64(dd，J＝7.91，1.29Hz，1H)7.32(d，J＝2.94Hz，1H)7.36(d，J＝2.94Hz，1H)7.41(dd，J＝8.82，2.21Hz，1H)7.72(s，1H)7.74(d，J＝1.47Hz，1H)7.80(d，J＝7.72Hz，1H)7.90-8.00(m，2H)8.05(s，1H)10.04(s，1H)11.41(s，1H)。MS(ESI-)m/z 506(M-H)⁺。

EXAMPLE 41 preparation of N- (6- (3-tert-butyl-2-chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide (Compound IB-L0-2.14).

Part a. preparation of 2-bromo-6-tert-butyl-4-iodoaniline.

A50 mL round bottom flask was charged with 2-bromo-6-tert-butylaniline [ according to Onitsuka et al. Organometallics, 25(5), 2006, pp 1270-. The mixture was cooled in an ice bath and iodine (1.444g, 5.69mmol) was added in portions. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was treated with aqueous sodium thiosulfate, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel, eluting with 5% ethyl acetate in hexane, to give an oil (1.2g, 65%).

Part b. preparation of 1-bromo-3-tert-butyl-2-chloro-5-iodobenzene.

To a mixture of tert-butyl nitrite (0.198mL, 1.5mmol) and copper (II) chloride (161mg, 1.2mmol) in acetonitrile (5mL) was added a solution of the product of part A (354mg, 1.0mmol) in acetonitrile (5 mL). The mixture was heated at 60 ℃ for 30min, cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on silica gel, eluting with 5% ethyl acetate in hexane to give the product (300mg, 81%).

Part c. preparation of 1- (3-bromo-5-tert-butyl-4-chlorophenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a 20mL microwave tube was added a solution of the product of part B (300mg, 0.803mmol), pyrimidine-2, 4(1H, 3H) -dione (99mg, 0.884mmol), N- (2-cyanophenyl) picolinamide (35.9mg, 0.161mmol), copper (I) iodide (15.30mg, 0.080mmol) and potassium phosphate (358mg, 1.687mmol) in DMSO (5 mL). The mixture was sealed, flushed with nitrogen and heated at 60 ℃ for 4 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified on silica gel eluting with 10% to 40% ethyl acetate in hexane to give a solid (175mg, 61%).

Part d. preparation of N- (6- (3-tert-butyl-2-chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide.

A5 mL microwave tube was charged with the product of part C (35.8mg, 0.10mmol), the product of example 2A, part B (38.2mg, 0.110mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (3.26mg, 5.00. mu. mol), and potassium phosphate (42.5mg, 0.200mmol) in THF/water (3 mL: 1 mL). The mixture was flushed with nitrogen for 5min and heated at 60 ℃ for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified on silica gel eluting with 1: 1 ethyl acetate/hexane to give a solid, using CH₂Cl₂Trituration with 1% methanol afforded a white solid (29mg, 55%), melting point: is more than 280 ℃.¹H NMR(300MHz，DMSO-d₆)δppm 1.53(s，9H)3.08(s，3H)5.69(d，J＝7.72Hz，1H)7.42(m，2H)7.52(dd，J＝8.46，1.84Hz，1H)7.56(d，J＝2.57Hz，1H)7.74(d，J＝1.84Hz，1H)7.84(d，J＝7.72Hz，1H)7.88(s，1H)7.91(d，J＝8.82Hz，1H)7.95(d，J＝9.19Hz，1H)10.04(s，1H)11.46(s，1H)。MS(ESI-)m/z 496(M-H)⁺。

Example 42 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] isoxazol-3-yl) methyl) methanesulfonamide (compound IB-L0-2.45).

Part a. preparation of N- ((6-bromobenzo [ d ] isoxazol-3-yl) methyl) -N- (4-methoxybenzyl) -methanesulfonamide.

To 6-bromo-3-methylbenzo [ d ]]CCl of isoxazole (1.0g, 4.72mmol)₄To a (25ml) refluxing solution were added 1-bromopyrrolidine-2, 5-dione (0.923g, 5.19mmol) and benzoic anhydride peroxide (0.114g, 0.472 mmol). The mixture was refluxed for 6h, then cooled to room temperature, filtered through Celite, and concentrated in vacuo. The crude product was purified by silica gel column chromatography using CH₂Cl₂As eluent, the dibromide was obtained as a solid (0.84g, 43%). To a solution of dibromide (0.20g, 0.687mmol) and N- (4-methoxybenzyl) methanesulfonamide (0.148g, 0.687mmol) in EtOH (3ml) was added an aqueous 1N NaOH solution (0.722ml, 0.722mmol) and the resulting mixture was stirred at 80 ℃ for 90 min. The mixture was partitioned between 0.1N aqueous HCl (10mL) and EtOAc (2X 10mL), and the organic layers were combined and washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by column chromatography on silica gel using 2: 3 EtOAc: hexane as eluent to give the title compound as an oil (65mg, 22%).

Part b. preparation of N- (4-methoxybenzyl) -N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] isoxazol-3-yl) methyl) methanesulfonamide.

A solution of the product of part A (56mg, 0.132mmol), bis (pinacolato) diboron (37mg, 0.145mmol) and potassium acetate (39mg, 0.395mmol) in 1, 4-dioxane (1.3mL) was degassed by bubbling nitrogen for 15 min. 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (3mg, 0.004mmol) was added and the resulting mixture was stirred at 80 ℃ for 16h, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1: 2 EtOAc: hexane as eluent to give the title compound as a colorless oil (49mg, 79%).

Part c. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] isoxazol-3-yl) methyl) -N- (4-methoxybenzyl) methanesulfonamide.

A solution of the product of example C (31.8mg, 0.079mmol), the product of part B (45mg, 0.095mmol) in EtOH (0.5mL), toluene (0.5mL), 1MNa by bubbling nitrogen through₂CO₃The mixture of aqueous solution (0.095mL, 0.095mmol) was degassed for 10 min. 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (2mg, 2.4. mu. mol) was added and degassing was continued with nitrogen for 5 min. The reaction mixture was sealed and heated in a microwave reactor at 100 ℃ for 1 h. The mixture was concentrated in vacuo and the crude product was taken up in 1: 9 MeOH: CHCl₃As eluent, purified by silica gel column chromatography. The title compound was obtained as a light brown solid (41mg, 83%).

Part d. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] isoxazol-3-yl) methyl) methanesulfonamide.

A solution of the product of part C (39mg, 0.063mmol) in TFA (0.5mL) was stirred at 40 ℃ for 6 h. TFA was removed in vacuo and the crude product was taken up in CHCl₃Purified by silica gel column chromatography with 4% MeOH as eluent to give the title compound (13mg, 41%). ¹H NMR(300MHz，CDCl₃)δ8.39(s，1H)7.74-7.82(m，2H)7.57(dd，J＝8.27，1.65Hz，1H)7.36(d，J＝7.72Hz，1H)7.25(d，J＝2.57Hz，1H)7.19(d，J＝2.94Hz，1H)5.82(dd，J＝7.72，2.21Hz，1H)5.25-5.33(m，1H)4.70(d，J＝6.25Hz，2H)3.29(s，3H)3.12(s，3H)1.45(s，9H)。

EXAMPLE 43 preparation of methyl 2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) hydrazinecarboxylate (compound IB-L0-2.24).

To a solution of the product of example 4, part B (0.05g, 0.124mmol) in MeOH (1ml) was added methyl carbamate (17mg, 0.185 mmol). The mixture was stirred at 60 ℃ for 16h, then concentrated in vacuo. The crude product used CH₂Cl₂Purified by silica gel column chromatography with 5% MeOH as eluent to give the title compound (44mg, 74%).¹H NMR(300 MHz，DMSO-d₆)δ11.40(s，1H)10.05(s，1H)7.78(d，J＝8.09Hz，1H)7.69(d，J＝7.72Hz，1H)7.45-7.57(m，2H)7.24-7.33(m，2H)5.64(d，J＝8.09Hz，1H)3.71(s，3H)3.28(s，3H)3.06-3.16(m，2H)2.78-2.88(m，2H)1.40(s，9H)。

EXAMPLE 44 preparation of 1- (3-tert-butyl-4-methoxy-5- (1-oxoisoindolin-5-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.30).

Part a. preparation of 5-bromo-2- (2, 4-dimethoxybenzyl) isoindolin-1-one.

To a solution of methyl 4-bromo-2- (bromomethyl) benzoate (1.0g, 3.25mmol) and (2, 4-dimethoxyphenyl) methylamine (0.65g, 3.90mmol) in THF (16mL) was added triethylamine (0.91mL, 6.5mmol), and the resulting mixture was stirred at room temperature for 16 h. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1: 4 EtOAc: hexane as eluent to give the title compound as a colorless solid (0.52g, 44%).

Part B preparation of 2- (2, 4-dimethoxybenzyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-1-one.

The product of part A (100mg, 0.276mmol) was subjected to the conditions of example 42, part B, to give the title compound as an oil (107mg, 95%).

Part c. preparation of 1- (3-tert-butyl-5- (2- (2, 4-dimethoxybenzyl) -1-oxoisoindolin-5-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part C (44mg, 0.111mmol) was subjected to the conditions of example 42, part C, to give the title compound (50mg, 81%).

Part d. preparation of 1- (3-tert-butyl-4-methoxy-5- (1-oxoisoindolin-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part C (48mg, 0.086mmol) in CH₂Cl₂(0.3ml) and TFA (0.6ml, 7.79mmol) solution was stirred at room temperature for 16h, then concentrated in vacuo. The crude product was used in CHCl₃Purified by silica gel column chromatography with 5% MeOH as eluent to give the title compound as a colorless solid (22mg, 63%).¹H NMR(300MHz，DMSO-d₆)δ11.41(d，J＝1.84Hz，1H)8.61(s，1H)7.72-7.83(m，3H)7.62-7.69(m，1H)7.29-7.36(m，2H)5.65(dd，J＝8.09，2.21Hz，1H)4.44(s，2H)3.25(s，3H)1.41(s，9H)。

EXAMPLE 45 preparation of N- (2- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) propan-2-yl) methanesulfonamide (compound IB-L0-2.41).

Part a. preparation of 6-bromo-1H-indene-3-carbonitrile.

To a solution of 5-bromo-2, 3-dihydro-1H-inden-1-one (1g, 4.74mmol) in dry THF (15ml) at-10 deg.C was added dropwise a solution of 2M lithium diisopropylamide in THF (0.242ml, 0.483 mmol). The resulting mixture was stirred at-10 ℃ for 15min, then diethyl cyanophosphonate (0.791ml, 5.21mmol) was added dropwise.After the addition, the mixture was warmed to room temperature and stirred at room temperature for 3 h. The mixture was cooled to-78 ℃ and boron trifluoride etherate (1.196ml, 9.52mmol) was added dropwise. After the addition, the mixture was stirred at-78 ℃ for 1h, then warmed to room temperature and stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was taken up in EtOAc (50mL) and H₂Partition between O (2X 50 mL). Na for organic layer₂SO₄Dried, filtered, concentrated in vacuo, and the crude product purified by silica gel column chromatography using 9: 1 EtOAc: hexane as eluent. The title compound was obtained as a brown solid (0.72g, 69%).

Part b. preparation of N- (2- (6-bromo-1H-inden-3-yl) propan-2-yl) methanesulfonamide.

Anhydrous cerium (III) chloride (0.224g, 0.909mmol) was flame dried in vacuo and placed in dry N₂In (1). Anhydrous THF (1.5ml) was added and the resulting mixture was stirred under nitrogen at 45 ℃ for 48 h. The mixture was cooled to room temperature and the product of part A (0.1g, 0.454mmol) was added. The resulting mixture was cooled to-78 deg.C and 1.5M lithium methylbromide complex (0.757ml, 1.136mmol) in Et was added dropwise over 15min ₂And (4) O solution. After the addition, the mixture was warmed to-20 ℃ and stirred for 24 h. Concentrated NH is added dropwise₄Aqueous OH (0.3mL), the mixture was warmed to room temperature, stirred for 30min, then filtered and washed with THF (2X 5 mL). The filtrate was concentrated in vacuo and the crude product used CH₂Cl₂Purified by column chromatography on silica gel with 5% MeOH as eluent to give a solid (23mg, 20%). To the solid (23mg, 0.091mmol) was added CH₂Cl₂To the solution (1mL) was added methanesulfonyl chloride (0.011mL, 0.137 mmol). The mixture was cooled to 0 ℃ and diisopropylethylamine (0.024ml, 0.137mmol) was added dropwise. The resulting mixture was stirred at room temperature for 90min, then in 0.1N HCl aqueous solution (2mL) and CH₂Cl₂(3X 2 mL). The organic layers were combined and washed with Na₂SO₄Drying, filtration, concentration in vacuo, and purification of the crude product by column chromatography on silica gel gave the title compound (17mg, 56%).

Part c. preparation of N- (2- (6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-inden-3-yl) propan-2-yl) methanesulfonamide.

The product of part C (50mg, 0.151mmol) was subjected to the conditions of example 42, part B to give the title compound as a colourless solid (37mg, 65%).

Part d. preparation of N- (2- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) propan-2-yl) methanesulfonamide.

The product of part C (35mg, 0.093mmol) was subjected to the conditions of example 42, part C, to give the title compound as a colorless solid (41mg, 84%).¹H NMR(300MHz，DMSO-d₆)δ11.40(s，1H)7.94(d，J＝8.09Hz，1H)7.78(d，J＝8.09Hz，1H)7.65(d，J＝1.50Hz，1H)7.56(s，1H)7.48(dd，J＝8.09，1.47Hz，1H)7.27(s，2H)6.48(s，1H)5.63(d，J＝8.09Hz，1H)3.43(s，2H)3.25(s，3H)2.63(s，3H)1.68(s，6H)1.41(s，9H)。

EXAMPLE 46 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide (compound IB-L0-2.11).

Part a. Preparing 6-bromobenzo [ b ] thiophene-2-carboxylic acid ethyl ester.

A solution of ethyl thioglycolate (0.65g, 5.42mmol), 4-bromo-2-fluorobenzaldehyde (1.0g, 4.93mmol) and triethylamine (1.25mL, 12.3mmol) in DMSO (5mL) was heated at 75 ℃ for 2 h. The mixture is in H₂O (50mL) and CH₂Cl₂Partition between (2X 50mL), combine the organic layers and add Na₂SO₄And (5) drying. The drying agent was filtered off and the solvent was removed in vacuo to give the title compound as an oil (1.29g, 92%).

Part B. preparation of 6-bromobenzo [ b ] thiophene-2-carboxylic acid.

To a solution of the product of part A (1.21g, 4.24mmol) in THF (10mL) was added LiOH (0.305g, 12.73mmol) in H₂O (4mL) solution and the resulting mixture was stirred at 40 ℃ for 2 h. The mixture is in H₂O (50mL) and CH₂Cl₂(50 mL). The aqueous layer was adjusted to pH 2 with 1N HCl and extracted with CH₂Cl₂(2X 50 mL). The organic layers were combined and washed with Na₂SO₄Drying, filtration, and concentration in vacuo afforded the title compound as an oil (1.04g, 95%).

Part C. preparation of 6-bromobenzo [ b ] thiophene.

The product of part B (0.70g, 2.73mmol) and DBU (1.35mL, 8.94mmol) were mixed in DMA (6mL) in a sealed tube and heated in a microwave reactor at 200 ℃ for 70 min. The resulting dark solution was diluted with 1M HCl (20mL) and CH₂Cl₂(2X 20 mL). The organic layers were combined and washed with Na₂SO₄Drying, filtering, vacuum concentrating, and using CH as crude product₂Cl₂Purification by column chromatography on silica gel as eluent gave the title compound as an oil (0.484g, 83%).

Part d. preparation of 6-bromo-3- (chloromethyl) benzo [ b ] thiophene.

To a solution of the product of part C (0.484g, 2.27mmol) in benzene (0.20mL) was added 37% aqueous formaldehyde (1mL) and concentrated HCl (1 mL). The resulting mixture was heated at 70 ℃ for 1h while HCl gas was bubbled through the mixture. The mixture is in H₂O (20mL) and CH₂Cl₂Partition between (2X 20mL), combine the organic layers and add Na₂SO₄Drying, filtering and vacuum concentrating. The crude product used CH₂Cl₂Purification by silica gel column chromatography gave the title compound as a waxy solid (0.49g, 82%).

Part e. preparation of N- ((6-bromobenzo [ b ] thiophen-3-yl) methyl) -N- (2, 4-dimethoxybenzyl) methanesulfonamide.

To the product of fraction D (275mg,1.05mmol) and N- (2.4-dimethoxybenzyl) -methanesulfonamide (284mg, 1.15mmol) in DMA (6mL) were added K ₂CO₃(160mg, 1.15mmol) and the mixture was stirred at room temperature for 3 h. The mixture is in H₂O (20mL) and Et₂Partition between O (2X 20mL), combine the organic layers, and add Na₂SO₄Drying, filtering and vacuum concentrating. The crude product used CH₂Cl₂Was purified by column chromatography on silica gel as eluent to give the title compound as a waxy solid (316mg, 64%).

Part f. preparation of N- (2, 4-dimethoxybenzyl) -N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide.

The product of part E (300mg, 0.64mmol) was subjected to the conditions of example 42, part B, to give the title compound as a waxy solid (248mg, 75%).

Part g. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) -N- (2, 4-dimethoxybenzyl) methanesulfonamide.

The product of part F (214mg, 0.414mmol) was subjected to the conditions of example 42, part C, to give the title compound as a pale yellow solid (238mg, 87%).

Preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide.

To the product of part G (230mg, 0.34mmol) in CH₂Cl₂Trifluoroacetic acid (0.5mL) was added to the solution (4mL), and the mixture was stirred at room temperature for 30 min. CH for solution₂Cl₂Diluted (10mL) with saturated NaHCO₃Aqueous solution (2X 10 mL). Na for organic layer₂SO₄Drying, filtering, vacuum concentrating, purifying the crude product by silica gel column chromatography using CH₂Cl₂Eluted with 3% MeOH to give the title compound as an off-white solid (149 m)g，84％)。¹H NMR(300MHz，DMSO-d₆)δ11.41(s，1H)8.16(d，J＝1.10Hz，1H)8.02(d，J＝8.46Hz，1H)7.79(d，J＝7.72Hz，1H)7.71(s，1H)7.60-7.66(m，2H)7.29-7.38(m，2H)5.65(d，J＝7.72Hz，1H)4.44(d，J＝5.88Hz，2H)3.24(s，3H)2.95(s，3H)1.42(s，9H)。

EXAMPLE 47 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1, 2, 3, 4-tetrahydroisoquinolin-6-yl) methanesulfonamide (compound IB-L0-2.19).

Part a. preparation of 1- (3-amino-5-tert-butyl-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

To the product of example 5, part F (170mg, 0.534mmol) and triethylamine (223. mu.L, 1.6mmol) in THF (5mL) was added diphenyl phosphorazidate (173. mu.L, 0.80 mmol). The resulting mixture was stirred at room temperature for 1h, then at 45 ℃ for 1 h. Water (280. mu.L) was added, and the resulting mixture was stirred at 50 ℃ for 1 hour, and then at room temperature for 16 hours. Solution H₂Dilute O (10mL) and filter the resulting solid. The solid was suspended in 1M aqueous HCl and filtered to give the amine product as the HCl salt. The salt is suspended in NaHCO ₃Aqueous (20mL), extracted with EtOAc (2X 20 mL). The organic layers were combined and washed with Na₂SO₄Drying, filtration, and concentration in vacuo afforded the title compound as a colorless solid (55mg, 36%).

Part b. preparation of 1- (3-tert-butyl-4-methoxy-5- (6-nitro-3, 4-dihydroisoquinolin-2 (1H) -yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part A (100mg, 0.28mmol) and 2- (2- (methylsulfonyloxy) -ethyl) -4-nitrobenzyl methanesulfonate (N-ethyl-N-methyl-4-nitrobenzyl methanesulfonate: (N-ethyl-N-methyl-N-propyl-196mg, 0.68mmol) was stirred in anhydrous DMA (4mL) at 80 ℃ for 18 h. Cooling the mixture in H₂Partition between O (20mL) and EtOAc (2X 20mL), combine the organic layers and work with Na₂SO₄Drying, filtering and vacuum concentrating. The residue is suspended in CH₂Cl₂In (1), unreacted aniline raw material is removed by filtration. The filtrate was concentrated in vacuo and the crude product was purified by silica gel column chromatography over CH₂Cl₂Eluted with 1% MeOH to give the title compound as a pale yellow solid (39.3mg, 31%).

Part c. preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1, 2, 3, 4-tetrahydroisoquinolin-6-yl) methanesulfonamide.

To the product of part B (35mg, 0.078mmol) in THF (0.5mL), MeOH (0.5mL), and H₂To a solution of O (0.25mL) were added iron powder (17.4mg, 0.41mmol) and NH ₄Cl (6.2mg, 0.12mmol), and the resulting mixture was stirred at 70 ℃ for 1 h. The hot mixture was filtered through Celite, rinsing with THF and MeOH. The filtrate was concentrated and dried in vacuo to give a solid. To the solid (32mg, 0.076mmol) and pyridine (26. mu.L, 0.32mmol) in CH₂Cl₂To the solution (1.5mL) was added methanesulfonyl chloride (7.7. mu.L, 0.099 mmol). The mixture was stirred at room temperature for 1h, then concentrated in vacuo. The crude product was purified by silica gel column chromatography using CH₂Cl₂Eluted with 5% MeOH to give the title compound as a pale yellow solid (7mg, 19%).¹H NMR(300MHz，DMSO-d₆)δ7.71(d，J＝8.09Hz，1H)7.14-7.21(m，1H)7.05-7.12(m，3H)6.98(d，J＝2.57Hz，1H)5.65(d，J＝7.72Hz，1H)4.18(s，2H)3.86(s，3H)3.03(t，J＝4.23Hz，2H)2.99(s，3H)1.38(s，9H)。

EXAMPLE 48 preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) isoindolin-5-yl) methanesulfonamide (compound IB-L0-2.79).

Part a. preparation of (4-nitro-1, 2-phenylene) bis (methylene) dimethanesulfonate.

To a solution of 4-nitrophthalic acid (500mg, 2.37mmol) in THF (24mL) was added dropwise 1M BH at room temperature₃THF complex solution (9.95mL, 9.95 mmol). The solution was stirred at 65 ℃ for 1h and then cooled to room temperature. MeOH (1mL) was added to the mixture, the mixture was stirred for 30min, and concentrated in vacuo. The residue was partitioned between 1M aqueous HCl (20mL) and EtOAc (2X 20mL), and the organic layers were combined and washed with Na ₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by silica gel column chromatography using CH₂Cl₂Eluted with 3% MeOH to give an oil (253mg, 58%). To oil (250mg, 2.37mmol) and triethylamine (438 μ L, 3.14mmol) in dry CH₂Cl₂To the solution (30mL) was added dropwise methanesulfonyl chloride (234. mu.L, 3.0mmol) at 0 ℃. The solution was stirred at room temperature for 18h in 1M aqueous HCl (20mL) and CH₂Cl₂(2X 20 mL). The organic layers were combined and washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by silica gel column chromatography using CH₂Cl₂Elution gave the title compound (150mg, 32%).

Part b. preparation of 1- (3-tert-butyl-4-methoxy-5- (5-nitroisoindolin-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a solution of the product of part A (110mg, 0.324mmol) and the product of part A of example 47 (113mg, 0.389mmol) in anhydrous 1, 4-dioxane (4mL) was added sodium bicarbonate (60mg, 0.71mmol) and diisopropylethylamine (142. mu.L, 0.81mmol) and the resulting mixture was stirred at 95 ℃ for 16 h. The mixture was dissolved in 0.5M aqueous HCl (10mL) and CH₂Cl₂Partition between (2X 10mL), combine the organic layers and add Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by silica gel column chromatography using CH ₂Cl₂1 in (1)% MeOH elution afforded the title compound as a pale yellow solid (110mg, 78%).

Preparation of N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) isoindolin-5-yl) methanesulfonamide.

The product of part B (100mg, 0.25mmol) was subjected to the conditions of example 47, part C to give the title compound as an off-white solid (53mg, 45%).¹H NMR(300MHz，DMSO-d₆)δ11.37(s，1H)9.70(s，1H)7.71(d，J＝7.72Hz，1H)7.34(d，J＝8.09Hz，1H)7.23(d，J＝1.84Hz，1H)7.13(dd，J＝8.09，1.84Hz，1H)6.98(d，J＝2.57Hz，1H)6.81(d，J＝2.21Hz，1H)5.62(d，J＝7.72Hz，1H)4.52(s，2H)4.50(s，2H)3.63(s，3H)2.98(s，3H)1.38(s，9H)。

EXAMPLE 49 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide (compound IB-L0-2.13).

Part a. preparation of 5-bromo-1- (trimethylsilyloxy) -2, 3-dihydro-1H-indene-1-carbonitrile.

To 5-bromo-2, 3-dihydro-1H-inden-1-one (10.0g, 47.4mmol) and N-methyl-morpholine N-oxide (1.67g, 14.21mmol) in CH₂Cl₂To the solution (50ml) was added trimethylsilyl cyanide (7.05g, 71.1mmol) and the resulting solution was stirred at room temperature for 72h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography using 5% EtOAc in hexane as eluent to give the title compound as a colorless liquid (12.65g, 86%).

Part b. preparation of 1- (aminomethyl) -5-bromo-2, 3-dihydro-1H-inden-1-ol.

To the product of part A (18.44g, 59.4mmol) in anhydrous Et at 0 deg.C under nitrogen₂1M LiAlH is dripped into O (250mL) solution within 1h₄Et (E) of₂O (62.4mL, 62.4mmol) solution. After the addition, the mixture was warmed to room temperature and stirred at room temperature for 2 h. The mixture was cooled in an ice bath, while H was added dropwise₂O (4.3mL), then 15% NH was added₄Aqueous OH (4.3mL) and then H was added₂O (13 mL). The mixture was stirred at room temperature for 15min, then filtered through Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo and the residue suspended in Et₂O (40mL) to give a precipitate, which was filtered and dried to give the title compound as a colorless solid (10.0g, 70%).

Part c. preparation of (6-bromo-1H-inden-3-yl) methylamine hydrochloride.

To a solution of the product of part B (10.0g, 41.3mmol) in MeOH (100mL) was added 6N aqueous HCl (125mL), and the mixture was stirred at 70 deg.C for 3h, then cooled to room temperature. MeOH was removed in vacuo to give a precipitate which was collected by filtration and washed with H₂O wash and dry in vacuo to afford the title compound as a colorless solid (9.89g, 92%).

Part d. preparation of N- ((6-bromo-1H-inden-3-yl) methyl) methanesulfonamide.

To the product of part C (6.46g, 24.8mmol) in anhydrous CH₂Cl₂To the suspension (260mL) was added methanesulfonyl chloride (3.86mL, 49.6mmol) and diisopropylethylamine (13.0mL, 74.4mmol), and the resulting mixture was stirred at room temperature for 10 h. The solution was washed with 1N aqueous HCl (2X 300mL) and the organic layer was Na ₂SO₄Drying, filtering and vacuum concentrating. The residue is suspended in Et₂O (100mL) gave a precipitate, which was collected by filtration and dried to give the title compound as a colorless solid (6.25g, 83%).

Part e. preparation of N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-inden-3-yl) methyl) methanesulfonamide.

A solution of the product of part D (2.0g, 6.62mmol), bis (pinacolato) diboron (1.85g, 7.28mmol), potassium acetate (1.95g, 19.86mmol) and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.27g, 0.331mmol) in anhydrous 1, 4-dioxane (80mL) was stirred at 95 ℃ for 8h under nitrogen. The mixture was cooled, filtered through Celite, washed with EtOAc (2X 20mL), and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1: 2 EtOAc: hexane as eluent to give the title compound as a colorless oil (2.02g, 87%).

Part f. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide.

The product of part E (3.14g, 8.99mmol), the product of example C (3.78g, 9.44mmol), tripotassium phosphate (3.82, 17.98mmol), 1, 3, 5, 7-tetramethyl-2, 4, 8-trioxa-6-phospha-6-phenyl-adamantane (Cytec [ 97739-46-3) ]) A mixture of (105mg, 0.36mmol) and tris (dibenzylideneacetone) -dipalladium (0) (165mg, 0.18mmol) was placed under nitrogen. THF (45mL) and H, which had been degassed by bubbling argon for 10min, were added to the mixture through a conduit₂Mixture of O (15 mL). The resulting mixture was degassed by bubbling argon for an additional 15 min. The mixture was stirred at 50 ℃ for 1.5h while argon continued to bubble through the solution. An additional solution of tris (dibenzylideneacetone) dipalladium (0) (55mg, 0.6mmol) in THF (2mL) was added and the mixture was stirred at 50 ℃ for 1 h. The mixture was cooled to room temperature over CH₂Cl₂(300mL) and 1N HCl aqueous solution (150 mL). To the orange organic layer was added 3-mercaptopropyl-functionalized silica gel (10g, Aldrich) and MgSO₄The mixture was stirred at room temperature for 16h, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3: 1 EtOAc: hexane as eluent to give the title compound as a colorless solid (2.7g, 61%).¹H NMR(300MHz，DMSO-d₆)δ11.40(s，1H)，7.78(d，J＝7.4Hz，1H)，7.66(s，1H)，7.60(d，J＝7.7Hz，1H)，7.50(m，2H)，7.25(m，2H)，6.56(m，1H)，5.64(dd，J＝2.2，7.7Hz，1H)，4.18(d，J＝5.1Hz，2H)，3.46(s，2H)，3.25(s，3H)，2.96(s，3H)，1.41(s，9H)。

EXAMPLE 50 preparation of N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methanesulfonyl hydrazide (compound IB-L0-2.31).

To the product of example 4, part C (100mg, 0.201mmol) in THF (2mL) and MeOH (2mL) was added 2 drops of 10% HCl in MeOH, followed by sodium cyanoborohydride (19mg, 0.302 mmol). The mixture was adjusted to pH 4 by addition of 10% HCl in MeOH, then stirred at room temperature for 1 h. The resulting mixture was dissolved in saturated aqueous sodium bicarbonate (5mL) and CH ₂Cl₂(20mL) and the organic layer was partitioned with Na₂SO₄Drying, filtering and concentrating. The crude product used CH₂Cl₂Purified by column chromatography on silica gel as eluent to afford the title compound as a colorless solid (58mg, 58%).¹H NMR(300MHz，DMSO-d₆)δ11.39(s，1H)，8.18(d，J＝3.7Hz，1H)，7.77(d，J＝7.7Hz，1H)，7.51(d，J＝8.1Hz，1H)，7.38(m，2H)，7.27(d，J＝2.6Hz，1H)，7.21(d，J＝2.9Hz，1H)，5.63(d，J＝7.7Hz，1H)，5.25(m，1H)，4.39(m，1H)，3.27(s，3H)，2.98(m，1H)，2.83(s，3H)，2.78(m，1H)，2.22(m，1H)，2.07(m，1H)，1.40(s，9H)。

EXAMPLE 51 preparation of 1- (3-tert-butyl-5- (1-hydroxy-2, 3-dihydro-1H-inden-5-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.36).

To the product of example 4, part B (150mg, 0.371mmol) in MeOH (3mL) and CH₂Cl₂To the solution (3mL) was added sodium borohydride (28mg, 0.742mmol) and the mixture was stirred at room temperature for 1 h. The mixture was dissolved in 1N aqueous HCl (10mL) and CH₂Cl₂(20mL) and the organic layer was partitioned with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product used CH₂Cl₂Purified by silica gel column chromatography with 5% MeOH as eluent to provide the title compound as a colorless solid (90mg, 60%).¹H NMR(300MHz，DMSO-d₆)：δ11.39(s，1H)，7.44(d，J＝4.0Hz，1H)，7.40(m，2H)，7.21(d，J＝2.6Hz，1H)，7.26(d，J＝2.6Hz，1H)，5.63(d，J＝8.1Hz，1H)，5.29(d，J＝5.9Hz，1H)，5.09(m，1H)，3.26(s，3H)，2.97(m，1H)，2.79(m，1H)，2.38(m，1H)，1.83(m，1H)，1.40(s，9H)。

EXAMPLE 52 preparation of 1- (3-tert-butyl-5- (2- (2, 5-dimethyl-1H-pyrrol-1-yl) benzo [ d ] thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.47).

Part a. preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) benzo [ d ] thiazole.

Reacting 6-bromobenzo [ d]A solution of thiazol-2-amine (5.75g, 25.1mmol), hexane-2, 5-dione (2.95mL, 25.1mmol) and PPTS (0.95g, 3.76mmol) in benzene (100mL) was refluxed for 16h while removing water with a Dean-Stark trap. The cooled mixture was poured into EtOAc (100mL) and saturated NaHCO ₃Aqueous solution (2X 100mL) and brine. Na for organic layer₂SO₄Drying, filtering and vacuum concentrating. The crude product was passed over silica using 9: 1 EtOAc: hexane as eluentPurification by gel column chromatography gave the title compound as an orange oil (6.46g, 84%).

Part B preparation of 2- (2, 5-dimethyl-1H-pyrrol-1-yl) -6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole.

A mixture of the product of part A (3.24g, 10.54mmol), bis (pinacolato) diboron (4.01g, 15.81mmol), bis (di-tert-butyl (hydroxy) phosphino) palladium (II) dichloride (0.264g, 0.527mmol) and potassium acetate (3.10g, 31.6mmol) in dry toluene (25mL) was degassed by bubbling nitrogen for 15min and then heated at reflux under nitrogen for 72 h. The cooled mixture was filtered through Celite, washing with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 9: 1 EtOAc: hexane as eluent to give the title compound (2.77g, 74%).

Part c. preparation of 1- (3-tert-butyl-5- (2- (2, 5-dimethyl-1H-pyrrol-1-yl) benzo [ d ] thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part B (405mg, 1.14mmol) was subjected to the conditions of example 42, part C, to give the title compound (430mg, 68%). ¹H NMR(300MHz，DMSO-d₆)δ11.43(d，J＝2.21Hz，1H)8.32(d，J＝1.47Hz，1H)8.12(d，J＝8.46Hz，1H)7.80(d，J＝7.72Hz，1H)7.76(dd，J＝8.46，1.84Hz，1H)7.35(q，J＝2.57Hz，2H)5.97(s，2H)5.66(dd，J＝7.72，2.21Hz，1H)3.30(s，3H)2.30(s，6H)1.43(s，9H)。

EXAMPLE 53 preparation of 1- (3- (2-aminobenzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxy-phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.27).

To the product of example 52 (4.0g, 8.0mmol) of trifluoroacetic acid (50mL) was added a few drops of H₂O, the resulting mixture was stirred at 80 ℃ for 2.5h, then concentrated in vacuo. Using concentrated NH₄The residue was neutralized with OH in MeOH, concentrated in vacuo and the crude product used 9: 1CH₂Cl₂MeOH was added as an eluent and purified by silica gel column chromatography to give the title compound (3.3g, 98%).¹H NMR(300MHz，DMSO-d₆)δ11.40(s，1H)7.81(s，1H)7.77(d，J＝8.09Hz，1H)7.57(s，1H)7.40(s，1H)7.33-7.38(m，1H)7.25(s，1H)5.60-5.69(m，1H)3.26(s，3H)1.40(s，9H)。

EXAMPLE 54 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-2-yl) methanesulfonamide (compound IB-L0-2.28).

To the product of example 53 (0.35g, 0.83mmol) in anhydrous CH₂Cl₂To the solution (50mL) was added methanesulfonyl chloride (194. mu.L, 2.49mmol) and pyridine (1.34mL, 16.6 mmol). The resulting mixture was stirred at room temperature for 16h and concentrated in vacuo. The crude product was used acetonitrile H₂A gradient of O (0.1% TFA) was purified by C-18 reverse phase HPLC to give the title compound (19mg, 4%).¹HNMR(300MHz，DMSO-d₆)δ13.09(s，1H)11.41(d，J＝1.84Hz，1H)7.96(d，J＝1.47Hz，1H)7.77(d，J＝8.09Hz，1H)7.57(dd，1H)7.42(d，J＝8.09Hz，1H)7.25-7.32(m，2H)5.64(dd，J＝8.09，2.21Hz，1H)3.25(s，3H)3.02(s，3H)1.40(s，9H)。

EXAMPLE 55 preparation of 1- (3- (benzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione (compound IB-L0-2.33).

To a solution of the product of example 53 (30mg, 0.071mmol) in anhydrous 1, 4-dioxane (3mL) under nitrogen was added isoamylnitrite (19. mu.L, 0.142 mmol). The resulting mixture was stirred under reflux for 1h and concentrated in vacuo. The crude product was used acetonitrile H₂A gradient of O (0.1% TFA) was purified by C-18 reverse phase HPLC to give the title compound (14mg, 48%).¹H NMR(300MHz，DMSO-d₆)δ11.42(d，J＝1.84Hz，1H)9.44(s，1H)8.34(d，J＝1.47Hz，1H)8.19(d，J＝8.46Hz，1H)7.79(d，J＝7.72Hz，1H)7.73(dd，J＝8.46，1.84Hz，1H)7.32-7.37(m，2H)5.65(dd，J＝7.91，2.39Hz，1H)3.24(s，3H)1.42(s，9H)。

EXAMPLE 56 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-2-yl) acetamide (compound IB-L0-2.49).

A mixture of the product from example 53 (30mg, 0.071mmol) and acetic anhydride (3mL) was stirred at 100 ℃ for 2h, then cooled to room temperature. The resulting solid was collected by filtration and washed with H₂O wash and dry to give the title compound as an off-white solid (29mg, 88%).¹H NMR(300MHz，DMSO-d₆)δ12.42(s，1H)11.41(d，J＝2.21Hz，1H)8.12(d，J＝1.47Hz，1H)7.82(d，J＝8.46Hz，1H)7.78(d，J＝8.09Hz，1H)7.61(dd，J＝8.46，1.84Hz，1H)7.31(q，J＝2.70Hz，2H)5.64(dd，J＝8.09，2.21Hz，1H)3.24(s，3H)2.22(s，3H)1.41(s，9H)。

EXAMPLE 57 preparation of 1- (3-tert-butyl-4-methoxy-5- (2- (propylamino) benzo [ d ] thiazol-6-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.46).

Part a. preparation of 1- (3-tert-butyl-5- (2-chlorobenzo [ d ] thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

To a mixture of the product from example 53 (50mg, 0.118mmol) and copper (II) chloride (24mg, 0.178mmol) in acetonitrile (3mL) was added tert-butyl nitrite (21. mu.L, 0.178mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1h, then brought to 65 ℃ and stirred for 2 h. The mixture was concentrated in vacuo using CH ₂Cl₂The 5% MeOH in (ll) was purified by silica gel column chromatography to give the title compound as an off-white solid (43mg, 82%).

Part b. preparation of 1- (3-tert-butyl-4-methoxy-5- (2- (propylamino) benzo [ d ] thiazol-6-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part A (50mg, 0.11mmol), 1-aminopropane (9. mu.L, 0.11mmol) and K₂CO₃A mixture of (15.6mg, 0.11mmol) of anhydrous DMF (5mL) was stirred at 100 ℃ for 24 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel using 2% MeOH in EtOAc as eluent to give the title compound as an off-white solid (21mg, 40%).¹H NMR(300MHz，DMSO-d₆)δ11.39(d，J＝1.84Hz，1H)8.12(t，J＝5.52Hz，1H)7.82(d，J＝1.47Hz，1H)7.77(d，J＝7.72Hz，1H)7.44(t，J＝9.01Hz，1H)7.37-7.41(m，1H)7.25(s，2H)5.63(dd，J＝7.91，2.02Hz，1H)3.33-3.38(m，2H)3.26(s，3H)1.56-1.69(m，2H)1.40(s，9H)0.94(t，J＝7.35Hz，3H)。

EXAMPLE 58 preparation of 1- (3-tert-butyl-4-methoxy-5- (3-methylbenzofuran-6-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.42).

Part a. preparation of methyl 2- (2-acetyl-5-bromophenoxy) acetate.

A solution of 1- (4-bromo-2-hydroxyphenyl) ethanone (1.35g, 6.28mmol) in anhydrous DMF (16mL) was treated with sodium hydride (377mg, 60% in oil, 226mg, 9.42mmol) several times and then stirred at room temperature for 30 min. The mixture was then treated with methyl bromoacetate (871 μ L, 1.45g, 9.48mmol) dropwise (solution warmed after complete addition) and then stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (4 ×) and saturated sodium chloride solution. Drying (Na) ₂SO₄) Concentrated in vacuo to afford a nearly colorless solid, which was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. These procedures provided the title compound as a colorless solid (1.47g, 82%).

Part b. preparation of 2- (2-acetyl-5-bromophenoxy) acetic acid.

A solution of the product of part A (1.47g, 5.12mmol) in tetrahydrofuran (26mL) was treated with 1.0N sodium hydroxide solution (6.7mL, 6.7mmol) and then stirred at room temperature for 3h, at which time the reaction was complete. The mixture was concentrated in vacuo to remove tetrahydrofuran, then diluted with water and cooled to 0 ℃. The mixture was acidified to pH 3 by addition of 1N hydrochloric acid solution, and the product was extracted with ethyl acetate. The organic layer was extracted with saturated sodium chloride solution and dried (Na)₂SO₄). Concentration in vacuo afforded the title compound as a colorless solid (1.36g, 97%).

Part c. preparation of 6-bromo-3-methylbenzofuran.

A solution of the product of part B (500mg, 1.83mmol) in acetic anhydride (9.2mL) was treated with sodium acetate (300mg, 3.66mmol) and then heated at reflux for 18 h. Cooling the mixtureAfter cooling to room temperature, it was diluted with toluene and concentrated under vacuum to azeotropically remove acetic anhydride. This process was repeated 3 times. The mixture was then diluted with ethyl acetate and stirred with saturated sodium bicarbonate solution for 1 h. The layers were separated and the organic layer was extracted with saturated sodium chloride solution. Drying (Na) ₂SO₄) Concentrated in vacuo to provide an amber oil which was purified by silica gel column chromatography eluting with 8-50% ethyl acetate in hexane. These procedures provided the title compound as a colorless liquid (316mg, 82%).

Part d. preparation of 4, 4, 5, 5-tetramethyl-2- (3-methylbenzofuran-6-yl) -1, 3, 2-dioxaborolan.

A mixture of the product of part C (303mg, 1.44mmol), bis (pinacolyl) diboron (401mg, 1.58mmol) and potassium acetate (423mg, 4.31mmol) in dry dioxane (5mL) was degassed by nitrogen sparging in a microwave tube for 15 min. The mixture was treated with 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (24mg, 0.029mmol) and then degassed for a further 5 min. The microwave tube was sealed and the mixture was heated at 90 ℃ for 18 h. The mixture was cooled, diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Drying the organic layer (Na)₂SO₄) And stirred with (3-mercaptopropyl) silica gel for 1 h. The mixture was filtered and concentrated in vacuo to afford a brown semisolid which was purified by silica gel column chromatography eluting with 8-40% ethyl acetate in hexane. These procedures provided the title compound as a colorless oil that slowly solidified on standing (307mg, 83%).

Part e. preparation of 1- (3-tert-butyl-4-methoxy-5- (3-methylbenzofuran-6-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione.

The product of fraction D (307mg, 1.19mmol), the product of example C (414mg, 1.03mmol), 1, 3, 5, 7-tetramethyl-2, 4, 8-trioxa-6-phospha-6-phenyl-adamantane (Cytec [ 97739-46-3-one) was sparged with nitrogen in a microwave tube]) A3: 1 tetrahydrofuran-water (8mL) solution of (15mg, 0.052mmol) and tripotassium phosphate (439mg, 2.07mmol) was degassed for 20 min. The mixture was treated with tris (dibenzylideneacetone) dipalladium (0) (12mg, 0.012mmol) and then degassed for a further 10 min. During this periodIn the meantime, the solution changed from an initial dark chestnut color to a green brown color. The microwave tube was sealed and the solution was heated at 50 ℃ for 56 h. The solution was cooled, diluted with ethyl acetate and acidified with 1M citric acid solution. The organic layer was extracted with saturated sodium chloride solution and dried (Na)₂SO₄) Then, the mixture was stirred with (3-mercaptopropyl) silica gel for 1 hour. After filtration, concentration in vacuo, the resulting residue was purified by column chromatography on silica eluting with 4-20% acetone in dichloromethane, followed by a second column chromatography on silica eluting with 20-100% ethyl acetate in hexane. These procedures provided the title compound as a colorless solid (355 mg).¹H NMR(300MHz，DMSO-d₆)：δ11.40(d， J＝1.84Hz，1H)7.74-7.92(m，2H)7.58-7.76(m，2H)7.46(dd，J＝8.09，1.47Hz，1H)7.30(q，J＝2.82Hz，2H)5.64(dd，J＝8.09，2.21Hz，1H)3.22(s，3H)2.25(s，3H)1.41(s，9H)。

EXAMPLE 59 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzofuran-3-yl) methyl) methanesulfonamide (compound IB-L0-2.18).

Part a. preparation of 6-bromo-3- (bromomethyl) benzofuran.

A refluxing solution of the product of section C (1.0g, 4.74mmol) and dibenzoyl peroxide (287mg, 1.19mmol) in chlorobenzene (24mL) was treated with N-bromosuccinimide (843mg, 4.74mmol) four times in 30 min. The mixture was then stirred at reflux for 2 h. The mixture was cooled, filtered, concentrated, and purified by silica gel column chromatography eluting with 7-30% chloroform in hexane. This procedure afforded the title compound as a pale yellow oil (438mg, 32%).

Part b. preparation of N- ((6-bromobenzofuran-3-yl) methyl) -N- (4-methoxybenzyl) methane-sulfonamide.

A solution of the product of part A (515mg, 1.78mmol), N- (4-methoxybenzyl) methane-sulphonamide (421mg, 1.95mmol) and potassium carbonate (260mg, 1.95mmol) in dry DMF (8.9mL) was stirred at 70 ℃ for 3 h. The mixture was cooled, diluted with ethyl acetate and extracted with water (4 ×). The organic layer was then extracted with saturated sodium chloride solution and dried (Na)₂SO₄). Concentration in vacuo afforded a beige solid. The material was purified by column chromatography on silica gel eluting with 20-100% ethyl acetate in hexane. These procedures provided the title compound as a colorless solid (224mg, 35%).

Preparation of N- (4-methoxybenzyl) -N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzofuran-3-yl) methyl) methanesulfonamide.

The product of part B (186mg, 0.44mmol) was subjected to the conditions of example 58, part D, to provide the title compound as a colorless solid (177mg, 86%).

Part d. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzofuran-3-yl) methyl) -N- (4-methoxybenzyl) methanesulfonamide.

A suspension of the product of part C (169mg, 0.36mmol), the product of example C (143mg, 0.36mmol) and 1.0M sodium carbonate solution (0.5mL, 0.50mmol) in 1: 1 ethanol-toluene (3mL) was degassed by nitrogen sparging in a microwave tube for 20 min. The solution was treated with 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) chloride dichloromethane complex (7mg, 9. mu. mol) and then degassed for a further 5 min. The microwave tube was sealed and the mixture was heated in a microwave oven at 100 ℃ for 1 h. The mixture was diluted with ethyl acetate and water and acidified with 1M citric acid solution. The organic layer was extracted with saturated sodium chloride solution and dried (Na)₂SO₄) And left overnight on (3-mercaptopropyl) silica gel. Filtration and concentration in vacuo afforded an off-white foam which was purified by column chromatography on silica eluting with 5-30% ethyl acetate in dichloromethane. This procedure afforded the title compound as a colorless solid (96mg, 43%).

Part e. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzofuran-3-yl) methyl) methanesulfonamide.

A solution of the product of part D (88mg, 0.14mmo) in dichloromethane (1.4mL) was treated with trifluoroacetic acid (1.4mL) and then stirred at room temperature for 18h, then at 40 ℃ for 2 h. The mixture was concentrated in vacuo to provide a dark purple brown foam which was subjected to silica gel column chromatography eluting with 5-50% ethyl acetate in dichloromethane to provide an impurity which was purified by reverse phase chromatography on a C-18 column eluting with 1% water-TFA/acetonitrile. This procedure provided the title compound as a solid (3.9 mg).¹H NMR(300MHz，DMSO-d₆)：δ11.31-11.48(m，1H)8.01(s，1H)7.68-7.94(m，2H)7.40-7.65(m，2H)7.10-7.38(m，2H)5.65(dd，J＝7.91，2.02Hz，1H)4.33(d，J＝5.88Hz，2H)3.23(s，3H)2.95(s，3H)1.41(s，9H)。

EXAMPLE 60 preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-methyl-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.25).

Part a. preparation of 5-bromo-1- (1, 3-dithian-2-yl) -2, 3-dihydro-1H-inden-1-ol.

A-30 ℃ solution of 1, 3-dithiane (11.96g, 99mmol) in anhydrous tetrahydrofuran (100mL) was treated with n-butyllithium (2.5M in hexane, 38.4mL, 96mmol) dropwise over 10min and then stirred at-15 ℃ for 2 h. The solution was then treated with a solution of 5-bromo-2, 3-dihydro-1H-inden-1-one (15g, 71.1mmol) in anhydrous tetrahydrofuran (250mL) over 1H, maintaining the temperature at-9 ℃ to 2 ℃. The mixture was then placed in a refrigerator at 2-8 ℃ for 18 h. The solution was concentrated in vacuo to provide a chestnut oil, which was washed with 1N hydrochloric acid The solution was treated and extracted with ether. The ether layer was extracted with saturated sodium chloride solution and dried (Na)₂SO₄) Concentrated in vacuo to give an amber oil (23.55 g).

Part b. preparation of 2- (5-bromo-2, 3-dihydro-1H-inden-1-ylidene) -1, 3-dithiane.

A solution of the product of part A (23.55g, 71.1mmol) in benzene (350mL) was treated with p-toluenesulfonic acid monohydrate (3.0g) and stirred under reflux for 1h while removing water with a Dean-Stark trap. The mixture was extracted with a saturated sodium bicarbonate solution, and then with a saturated sodium chloride solution. Drying (Na)₂SO₄) Concentration in vacuo afforded the product as an amber oil (22.27 g).

Part c. preparation of 5-bromo-2, 3-dihydro-1H-indene-1-carboxylic acid.

A solution of the product of part B (22.27g, 71.1mmol) in glacial acetic acid (375mL) was treated with concentrated hydrochloric acid solution (125mL) and then stirred under reflux for 3 h. The mixture was cooled and concentrated in vacuo by azeotroping acetic acid and water with toluene (3 ×). The resulting brown oil was filtered through a 70-230 mesh silica plug (silica volume about 1800mL) in a 2L sintered glass funnel, eluting with dichloromethane to remove non-polar impurities (especially 1, 3-propanedithiol), then the title compound was eluted with ethyl acetate to give a brown solid (9.85g, 58%).

Part d. preparation of 5-bromo-2, 3-dihydro-1H-indene-1-carboxylic acid methyl ester.

A suspension of the product of part C (9.85g, 40.9mmol) in methanol (400mL) was treated with 4N hydrochloride in 1, 4-dioxane (125mL) and the mixture was stirred at reflux for 8 h. The mixture was concentrated in vacuo to provide a brown oil which was purified by silica gel column chromatography eluting with 0-30% methyl tert-butyl ether in chloroform. These procedures provided the title compound as an amber oil (7.99g, 77%).

Part e. preparation of 5-bromo-1-methyl-2, 3-dihydro-1H-indene-1-carboxylic acid methyl ester.

Dropwise adding bis (trimethyl silyl) within 10minLithium alkyl) amide (1.0M in tetrahydrofuran, 9.55mL, 9.55mmol) A solution of the product of part D (2.03g, 7.96mmol) in anhydrous tetrahydrofuran (40mL) at-78 ℃ under nitrogen was treated. The solution was stirred at-78 ℃ for 45min and then treated with iodomethane (1.5mL, pre-dried by passage through an alkaline alumina plug). The mixture was then gradually warmed to room temperature and stirred for 18 h. The mixture was quenched by the addition of saturated ammonium chloride solution (2 mL). The mixture was concentrated in vacuo to remove tetrahydrofuran and the residue was diluted with ethyl acetate. The mixture was extracted with saturated ammonium chloride solution and saturated sodium chloride solution. Drying (Na) ₂SO₄) Concentration in vacuo gave the title compound as an amber oil (2.06g, 96%).

Part f. preparation of 5-bromo-1-methyl-2, 3-dihydro-1H-indene-1-carboxylic acid.

A solution of the product of part E (2.06g, 7.65mmol) and potassium trimethylsilanolate (5.5g 90%, 4.91g, 38.3mmol) in tetrahydrofuran (40mL) was stirred at reflux for 3 h. The mixture was cooled and concentrated in vacuo to remove tetrahydrofuran. The maroon residue was dissolved in water (about 175mL) and extracted with methyl tert-butyl ether. The aqueous phase was cooled to 0 ℃ and acidified to pH 3 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (2 ×), and then with saturated sodium chloride solution. Drying the solution (Na)₂SO₄) Treated with Darco G-60 and then filtered through Celite. The filtrate was concentrated in vacuo to provide the title compound as a pale yellow solid (1.93g, 99%).

Part g. preparation of 5-bromo-1-methyl-2, 3-dihydro-1H-indene-1-carboxamide.

A solution of part F of the product (1.56g, 6.12mmol) and DMF (473. mu.L, 447mg, 6.12mmol) in hexane (100mL) was treated with oxalyl chloride (1.61mL, 2.32g, 18.4mmol) and stirred at room temperature for 1 h. The mixture was treated with Celite, and then filtered through Celite. The filtrate was concentrated in vacuo, dissolved in acetone (75mL) and cooled to 0 ℃. The solution was treated with 28% aqueous ammonia (75mL), then stirred at 0 ℃ for 30min, then warmed to room temperature. The mixture was concentrated in vacuo and extracted with ethyl acetate. Extracting the organic layer with saturated sodium chloride solution, and drying (Na₂SO₄). Concentration in vacuo afforded the title compound as an oil (1.55g, 100%).

Part H. preparation of (5-bromo-1-methyl-2, 3-dihydro-1H-inden-1-yl) methylamine hydrochloride.

A solution of the product of part G (1.21G, 4.76mmol) in anhydrous tetrahydrofuran (8mL) was heated to gentle reflux in a flask fitted with a Vigrella column and a short path distillation head and treated with borane-dimethyl sulfide complex (904. mu.L, 723mg, 9.52mmol) dropwise. The resulting mixture was stirred at reflux for 2 h. The solution was cooled to room temperature, carefully treated with methanol until the bubbles disappeared, and then carefully treated with a 4N hydrochloric acid solution (4mL) in 1, 4-dioxane. The mixture was then concentrated in vacuo. A colorless solid was obtained, triturated with ether and collected by filtration. After drying in a vacuum oven at 50 ℃ for 2h, the title compound was obtained as a colourless solid (893mg, 68%).

Part i. preparation of (5-bromo-1-methyl-2, 3-dihydro-1H-inden-1-yl) methyl-carbamic acid tert-butyl ester.

A suspension of the product of part H (893mg, 3.23 mmol) in tetrahydrofuran (16mL) was treated with di-tert-butyl dicarbonate (846mg, 3.87mmol) and saturated sodium bicarbonate solution (7.2mL, ca. 6.46mmol) and then stirred at room temperature for 18H. The mixture was diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Drying the solution (Na) ₂SO₄) And (4) concentrating in vacuum. The residue was purified by flash chromatography, eluting with 5-40% ethyl acetate in hexane. These procedures provided the title compound as a colorless solid (1.03g, 94%).

Part j. preparation of tert-butyl (1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) methylcarbamate.

The product of part I (1.03g, 3.03mmol) was subjected to the conditions of example 58, part D, to provide the title compound as a colorless solid (977mg, 83%).

Part k. preparation of tert-butyl (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-methyl-2, 3-dihydro-1H-inden-1-yl) methylcarbamate.

The product of part J (965mg, 2.49mmol) was subjected to the conditions of example 59, part D, to provide the title compound as a colorless solid (618mg, 47%).

Part l. preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-methyl-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide.

The product of part K (446mg, 0.84mmol) was dissolved in 4N hydrochloric acid solution in dioxane (12mL) and then stirred at room temperature for 18 h. The resulting suspension of colorless solid was then concentrated in vacuo. This material was suspended in dichloromethane (5mL), cooled to 0 deg.C, and then treated successively with triethylamine (280. mu.L, 203mg, 2.01mmol) and methanesulfonyl chloride (81. mu.L, 120mg, 1.05 mmol). The mixture was stirred at 0 ℃ for 1h, then warmed to room temperature and diluted with dichloromethane. The mixture was extracted with 1M citric acid solution and then dried (Na) ₂SO₄) And (4) concentrating in vacuum. The residue was dissolved in 3: 1 tetrahydrofuran-water (8mL), treated with potassium carbonate (231mg, 1.68mmol), and then stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was diluted with water and then acidified to about pH 2 by the addition of 1M citric acid. The product was extracted with ethyl acetate and the organic layer was extracted with saturated sodium chloride solution. Drying (Na)₂SO₄) Concentrated in vacuo to afford a colorless solid, which is purified by silica gel column chromatography, eluting with 30-100% ethyl acetate in hexane. This procedure afforded the title compound as a colorless solid (184mg, 43%).¹H NMR(300MHz，DMSO-d₆)：δ11.39(s，1H)7.77(d，J＝7.72Hz，1H)7.14-7.48(m，5H)7.06(t，J＝6.62Hz，1H)5.63(d，J＝7.72Hz，1H)3.18-3.33(m，3H)2.96-3.15(m，2H)2.85-3.00(m，2H)2.70-2.87(m，3H)2.10-2.34(m，1H)1.63-1.90(m，1H)1.40(s，9H)1.20-1.34(m，3H)。

EXAMPLE 61 preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H) inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.12).

Part a. preparation of 5- (5-bromo-2, 3-dihydro-1H-inden-1-ylidene) -2, 2, 3, 3, 7, 7, 8, 8-octamethyl-4, 6-dioxa-3, 7-disilazane.

To a solution of the product from example 60, part C (1.2g, 4.98mmol) in dry THF (5mL) was added TBSCl (1.726g, 11.45mmol) and the resulting yellow solution was cooled to 0 ℃ in an ice bath. A1.0M solution of LiHMDS in THF (11.95mL, 11.95mmol) was added dropwise over 5min, and the resulting dark red solution was stirred at 0 ℃ for 90min, then at room temperature for 6 h. The solvent was removed in vacuo and the oily semisolid residue was treated with pentane (2X 35mL) to precipitate LiCl. The slurry was filtered and the solvent removed in vacuo to give the title compound as a brown oil (2.3 g).

Part b. preparation of 5-bromo-1-fluoro-2, 3-dihydro-1H-indene-1-carboxylic acid.

To 1-chloromethyl-4-fluoro-1, 1-diazabicyclo [2.2.2.]Octane bis (tetrafluoroborate) (Selectfluor, 2.26g, 6.37mmol) in CH₃CN (20mL) mixture was added the product of part A (2.3g, 4.90mmol) in CH₃CN (6mL) solution. The resulting yellow orange solution was stirred at room temperature overnight. The reaction mixture was poured into 50mL of 1N HCl (aq) and extracted with EtOAc (2X 35 mL). The organic extracts were combined and washed with 0.5N NaOH (3X 30 mL). The aqueous extracts were combined, washed with EtOAc (2X 25mL), and the mixture was adjusted to pH 1 with 5N HCl (10 mL). The resulting cloudy brown solution was extracted with EtOAc (2X 50mL), and the combined organic layers were washed with 10% NaCl and then treated with decolorizing carbon and stirred for 1 h. The mixture is mixed with anhydrous Na₂SO₄Drying, filtration through Celite and removal of the solvent in vacuo afforded the title compound as a yellow oil (0.8)4g)。

Part c. preparation of 5-bromo-1-fluoro-2, 3-dihydro-1H-indene-1-carbonyl chloride.

To the product of part B (0.95g, 3.67mmol) in CH₂Cl₂To the solution was added oxalyl chloride (0.96mL, 11.00mmol) followed by DMF (0.28 mL). The resulting bubbled solution was stirred at room temperature for 2h, filtered through Celite and the solvent removed in vacuo to give the title compound as a brown oil (0.99 g).

Part d. preparation of 5-bromo-1-fluoro-2, 3-dihydro-1H-indene-1-carboxamide.

To a solution of the product of part C (0.99g, 3.57mmol) in acetone (20mL) at 0 deg.C was added NH₄Aqueous OH (28%, 0.28mL, 3.57mmol) and the resulting dark brown mixture was stirred at 0 ℃ for 1 h. The reaction mixture was concentrated in vacuo and the residue partitioned between water and EtOAc (2X 50 mL). Combining the organic extracts with 1N H₃PO₄、10％NaHCO₃(aqueous solution), 10% NaCl wash, Na anhydrous₂SO₄Drying, filtering and vacuum concentrating. The brown solid was purified by silica gel column chromatography using CH₂Cl₂A MeOH solvent gradient (99/1-96/4). The title compound was obtained as a brown solid (0.205g, 22%).

Part e. preparation of (5-bromo-1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl-carbamic acid tert-butyl ester.

To a solution of the product of part D (0.234g, 0.907mmol) in anhydrous THF (5mL) at 80 deg.C was added borane-DMS complex (0.172mL, 1.813mmol) dropwise. The reaction flask was equipped with a short-path condenser, the mixture was stirred under reflux for 2h, and THF and DMS were collected. The mixture was then cooled to room temperature, MeOH (5mL) was added, followed by 4N Cl (5mL) in 1, 4-dioxane. The solvent was removed in vacuo to give a colorless solid (0.25g, 98%). The solid was dissolved in THF (5mL), triethylamine (0.137mL, 0.980mmol) was added to the solution, followed by di-tert-butyl dicarbonate (0.214g, 0.980 mmol). The turbid mixture was stirred at room temperature for 30min and 10% NaHCO was added ₃Aqueous solution (1 mL). To obtainThe resulting mixture was stirred at room temperature for 18h, then concentrated in vacuo to an oily residue. The residue was dissolved in EtOAc (50mL), washed with water, 1N H₃PO₄Washed with 10% NaCl and dried over Na₂SO₄And (5) drying. The drying agent was filtered off and the solvent was removed in vacuo to give the title compound as an oil (0.27g, 88%).

Part f. preparation of tert-butyl (1-fluoro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) methylcarbamate.

The product of part E (0.27g, 0.784mmol) was subjected to the conditions of example 42, part B to give the title compound as a brown solid (0.159g, 52%).

Part g. preparation of tert-butyl (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methylcarbamate.

To the product of part F (0.159g, 0.405mmol), the product of example C (0.162g, 0.405mol), a solution of 1, 3, 5, 7 tetramethyl-2, 4, 8-trioxa-6-phospha-6-phenyladamantane (PA-Ph, CAS 97739-46-3) (3.55g, 0.012mmol) in THF (3mL) was added K₃PO₄(0.181g, 0.851mmol) and water (1mL) followed by the addition of tris (dibenzylideneacetone) dipalladium (0) catalyst (3.71mg, 0.00405 mmol). The resulting mixture was degassed by bubbling nitrogen for 20min, and then stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (50mL) and 1N H ₃PO₄、10％NaHCO₃Washed with 10% NaCl and dried over Na₂SO₄And (5) drying. Filtering the mixture, removing the solvent in vacuo to give a brown oil, purifying by silica gel column chromatography using 98/2CH₂Cl₂MeOH elution. The title compound was isolated as a colorless solid (0.118g, 54%).

Part H. preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide.

The product of part G (0.118G, 0.219mmol) was dissolved in 4N HCl (2mL) in 1, 4-dioxane and stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue suspended in CH₂Cl₂Evaporation (2X 4mL) gave a colorless solid (0.10g, 96%). Dissolving the solid in CH₂Cl₂(1mL), the resulting slurry was stirred in an ice bath. Triethylamine (0.059mL, 0.422mmol) was added to the slurry to produce a clear solution, to which methanesulfonyl chloride (0.02mL, 0.253mmol) was added. The resulting mixture was stirred in an ice bath for 1 h. Reaction mixture with CH₂Cl₂Diluting with 50mL of 1N H₃PO₄、10％NaHCO₃Washed with 10% NaCl and dried over Na₂SO₄And (5) drying. The drying agent is filtered off and the solvent is removed in vacuo leaving the crude product which is purified by column chromatography on silica gel eluting with a gradient of 1: 1 to 3: 7 hexanes: EtOAc. The title compound was obtained as a colorless solid (64mg, 62%). ¹H NMR(300MHz，DMSO-d₆)δ11.39(s，1H)7.77(d，J＝7.72Hz，1H)7.30-7.48(m，3H)7.12-7.32(m，3H)5.63(d，J＝7.72Hz，1H)3.27(s，3H)2.94-3.08(m，4H)2.91(s，3H)2.17-2.38(m，1H)1.76-1.97(m，1H)1.40(s，9H)。

EXAMPLE 62 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methanesulfonamide (compound IB-L0-2.43).

Part a. preparation of N- (3-bromophenylethyl) -2, 2, 2-trifluoroacetamide.

To a solution of 2- (3-bromophenyl) ethylamine (10g, 50.0mmol) in dichloromethane (200ml) at 0 ℃ was added 2, 6-lutidine (6.40ml, 55.0mmol), then trifluoroacetic anhydride (7.77ml, 55.0mmol) was added dropwise and the reaction stirred at room temperature overnight.Adding water at 0 deg.C, reacting with 1M HCl, H₂O and saturated NaHCO₃And (4) washing with an aqueous solution. The organics were over MgSO₄Drying, filtration, and concentration afforded the title compound as a brown solid (14.7g, 99%).

Part b. preparation of 1- (6-bromo-3, 4-dihydroisoquinolin-2 (1H) -yl) -2, 2, 2-trifluoro-ethanone.

To a mixture of the product of part A (14.70g, 49.6mmol) and paraformaldehyde (2.39g, 80mmol) was added a mixture of acetic acid (81ml) and sulfuric acid (53.7ml) at room temperature. The suspension was stirred for 60h, during which time it became a solution. The reaction was poured into cold water. The reaction was diluted with ethyl acetate, water, saturated NaHCO₃Aqueous solution and brine. With MgSO ₄The organic layer was dried, filtered, and concentrated to provide the title compound as a colorless oil containing 8-bromo isomer (10.5g, 67%).

Part c. preparation of 6-bromo-1, 2, 3, 4-tetrahydroisoquinoline.

To a solution of the product of part B (9.5g, 30.8mmol) in methanol (231ml) and water (77ml) was added potassium carbonate (8.52g, 61.7mmol) at room temperature and the reaction stirred at room temperature for 30 min. The reaction was diluted with water and 25% isopropanol in chloroform and the pH adjusted to 9 with 1N HCl. The mixture was extracted twice with 25% isopropanol in chloroform. The organic layers were combined and MgSO₄Drying, filtration and concentration gave the title compound containing 8-bromo isomer (6.55g, quantitative).

Part d. preparation of 6-bromo-2-nitroso-1, 2, 3, 4-tetrahydroisoquinoline.

To a solution of the product of part C (6.55g, 30.9mmol) in acetic acid (61.8ml) and 3N aqueous hydrochloric acid (10.29ml, 30.9mmol) was added dropwise 1.9M sodium nitrite (20.64ml, 39.2mmol) at 0 deg.C and the reaction stirred at room temperature overnight. The solvent was evaporated and the reaction was performed with 25% isopropanol and saturated NaHCO in chloroform₃And (5) diluting the aqueous solution. The aqueous layer was extracted twice with 25% isopropanol in chloroform. The organic layers were combined and MgSO₄Drying, filtering, and concentrating to obtain the title compound containing There is the 8-bromo isomer (6.97g, 94%).

Part e. preparation of 6-bromo-3, 4-dihydroisoquinolin-2 (1H) -amine.

To a solution of the product of part D (0.5g, 2.074mmol) in methanol (4.15ml) was added zinc (0.542g, 8.30mmol), the reaction cooled to 0 ℃ and AcOH (4.15ml) was added dropwise. The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was filtered and the solid was washed with methanol. The filtrate was evaporated, the residue diluted with water and 25% isopropanol in chloroform, and saturated NaHCO was added₃An aqueous solution. The white solid was removed by filtration and the aqueous layer was extracted twice with 25% isopropanol in chloroform. The organic layers were combined and MgSO₄Drying, filtration and concentration gave the title compound containing 8-bromo isomer (0.472g, quantitative).

Part f. preparation of tert-butyl 6-bromo-3, 4-dihydroisoquinolin-2 (1H) -ylcarbamate.

A solution of the product of part E (0.472g, 2.078mmol) in THF (20.78ml) was cooled to 0 deg.C, di-tert-butyl dicarbonate (0.531ml, 2.286mmol) was then added and the reaction stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (lower R isolated)_fProduct), using a gradient starting with dichloromethane and ending with 10% ethyl acetate in dichloromethane, the title compound was obtained (49mg, 73%).

Part g. preparation of tert-butyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -ylcarbamate.

A solution of the product of part F (100mg, 0.306mmol), bis (pinacolyl) diboron (85mg, 0.336mmol) and potassium acetate (57.3. mu.l, 0.917mmol) in 1, 4-dioxane (3.0mL) was degassed by bubbling nitrogen for 15 min. 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (11.18mg, 0.015mmol) was added and the resulting mixture was stirred at 95 ℃ for 16 h. The cooled solution was diluted with 25% isopropanol in chloroform and washed with water. With MgSO₄The organic layer was dried, filtered and concentrated in vacuo. The product was passed through silica gelPurification by column chromatography eluting with a gradient starting with dichloromethane and ending with 25% ethyl acetate in dichloromethane afforded the title compound (70mg, 61%).

Part H. preparation of tert-butyl 6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -3, 4-dihydroisoquinolin-2 (1H) -ylcarbamate.

A solution of the product of example C (74.8mg, 0.187mmol), the product of part G (70mg, 0.187mmol) in EtOH (1.0mL), toluene (1.0mL), 1MNa by bubbling nitrogen through ₂CO₃A mixture of aqueous solution (281. mu.l, 0.281mmol) was degassed for 10 min. 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (6.84mg, 9.35. mu. mol) was added and degassing was continued with nitrogen for 5 min. The reaction mixture was sealed and heated at 78 ℃ for 16 h. The reaction was cooled, diluted with 25% isopropanol in chloroform and washed with water. The organics were over MgSO₄Drying, filtering and concentrating. The crude product was purified by column chromatography on silica eluting with a gradient of starting with dichloromethane and ending with ethyl acetate to give the title compound (53mg, 54%).

Part i. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methanesulfonamide.

To a solution of the product of part H (25mg, 0.048mmol) in dichloromethane (0.5mL) was added TFA (0.5mL) at room temperature, the reaction was stirred for 30min, then concentrated in vacuo. The residue was diluted with 25% isopropanol in chloroform and saturated NaHCO₃And (4) washing with an aqueous solution. With MgSO₄The organic layer was dried, filtered, and concentrated to give a solid (17.8mg, 88%). To a solution of the solid in pyridine (0.5mL) was added methanesulfonyl chloride (12.6. mu.L, 0.162mmol) at 0 ℃ and the reaction was stirred at room temperature for 90 min. Methanol was added and the reaction stirred for 10 min. The residue was diluted with 25% isopropanol in chloroform and saturated NaHCO ₃And (4) washing with an aqueous solution. With MgSO₄The organic layer was dried, filtered, concentrated and the product purified by column chromatography on silica gel with a gradient starting with dichloromethane and endingEluting with ethyl acetate, the title compound was obtained (11mg, 52%).¹H NMR(300MHz，DMSO-d₆)δ11.39(s，1H)8.53(s，1H)7.76(d，J＝7.72Hz，1H)7.11-7.42(m，5H)5.63(d，J＝7.72Hz，1H)4.04(s，2H)3.28(s，3H)3.10(d，J＝5.52Hz，2H)2.98(s，3H)2.90-3.05(m，2H)1.40(s，9H)。

Example 63 preparation of N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide (compound IB-L0-2.65).

Part a. preparation of N- ((6- (3-bromo-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide.

The product of example 18, part C (0.242g, 0.573mmol) and the product of example 49, part E (0.200g, 0.57mmol) were subjected to the conditions of example 49, part F to give the title compound as an off-white solid (0.104g, 35%).

Part b. preparation of N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide.

A solution of the product of part A (25.2mg, 0.049mmol) in 3: 1v/v THF-water (1.3mL) was mixed at room temperature with furan-2-ylboronic acid (6.91mg, 0.062mmol) and potassium phosphate (16.84mg, 0.097mmol) in a microwave tube. To this was added 1, 1' -bis (di-tert-butyl-phosphino) ferrocene palladium dichloride (1.65mg, 2.53. mu. mole). The tube was sealed and the resulting mixture was flushed with nitrogen for 4min and then heated in an oil bath at 50 ℃ for 16.5 h. The reaction mixture was partitioned between dilute HCl and ethyl acetate and dried (MgSO) ₄) The organic phase was concentrated in vacuo. The residue is purified by chromatography on silica gel (Ethyl acetate-hexanes) to give the title compound as an off-white solid (11.4mg, 46%).¹H NMR(300MHz，DMSO-d₆)δ11.45(s，1H)7.80-7.89(m，2H)7.73-7.79(m，2H)7.56-7.63(m，2H)7.50(t，J＝6.07Hz，1H)7.38(d，J＝2.94Hz，1H)7.09(d，J＝3.31Hz，1H)6.68(dd，J＝3.68，1.84Hz，1H)6.58(s，1H)5.68(d，J＝7.72Hz，1H)4.19(d， J＝5.15Hz，2H)3.48(s，2H)3.34(s，3H)2.96(s，3H)。

EXAMPLE 64 preparation of N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) -1H-inden-3-yl) methyl) methanesulfonamide (compound IB-L0-2.63).

The product of example 63, part A (26.5mg, 0.051mmol) was reacted with thiophen-2-ylboronic acid (8.3mg, 0.065mmol) according to the description of example 63, part B to give the title compound as an off-white solid (8.6mg, 32%).¹H NMR(300MHz，DMSO-d₆)δ11.47(s，1H)7.86(d，J＝7.72Hz，2H)7.55-7.78(m，5H)7.50(t，J＝6.25Hz，1H)7.38(d，J＝2.57Hz，1H)7.16-7.21(m，1H)6.58(s，1H)5.69(d，J＝7.72Hz，1H)4.19(d，J＝4.78Hz，2H)3.48(s，2H)3.30(s，3H)2.96(s，3H)。

Example 65 preparation of N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-3-yl) phenyl) -1H-inden-3-yl) methyl) methanesulfonamide (compound IB-L0-2.62).

According to the embodimentDescription of part B example 63, part A product (25.9mg, 0.050mmol) was reacted with thiophen-3-ylboronic acid (8.1mg, 0.063mmol) to give the title compound as an off-white solid (8.6mg, 33%).¹H NMR(300MHz，DMSO-d₆)δ11.45(d，J＝1.84Hz，1H)7.93(d，J＝2.94Hz，1H)7.87(d，J＝7.72Hz，1H)7.53-7.75 (m，6H)7.49(t，J＝6.25Hz，1H)7.39(d，J＝2.57Hz，1H)6.57(s，1H)5.68(dd，J＝7.91，2.02Hz，1H)4.19(d，J＝5.15Hz，2H)3.47(s，2H)3.21(s，3H)2.96(s，3H)。

Example 66 preparation of N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide (compound IB-L0-2.67).

The product of example 63, part A (25.9mg, 0.050mmol) was reacted with furan-3-ylboronic acid (7.2mg, 0.064mmol) according to the description of example 63, part B to give the title compound as an off-white solid (10.6mg, 45%).¹H NMR(300MHz，DMSO-d₆)δ11.46(s，1H)7.84(d，J＝8.09Hz，1H)7.80(t，J＝1.84Hz，1H)7.68-7.75(m，2H)7.54-7.64(m，2H)7.50(t，J＝6.07Hz，1H)7.35(d，J＝2.57Hz，1H)7.08(d，J＝1.47Hz，1H)6.57(s，1H)5.68(d，J＝8.09Hz，1H)3.47(s，2H)3.30(s，3H)2.96(s，3H)。

EXAMPLE 67 preparation of 1- (3-tert-butyl-4-methoxy-5- (1- (methylsulfonyl) indolin-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.32).

Part a. preparation of 5-bromo-1- (methylsulfonyl) indoline.

To DMF (5.0ml) was added sodium hydride (53mg, 1.3mmol) and the solution stirred at room temperature for 30 min. 5-Bromoindoline (240mg, 1.2mmol) was added and the solution was stirred at room temperature for 30 min. Methanesulfonyl chloride (94. mu.l, 1.2mmol) was added and the solution was stirred at room temperature overnight and then concentrated in vacuo. The crude product was purified by silica gel column chromatography using 2% CH₃OH/CHCl₃Elution gave the title compound (202mg, 60%).

Part b. preparation of 1- (methylsulfonyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline.

The product of part A (192mg, 0.70mmol) was subjected to the conditions described for example 42, part B to give the title compound (114mg, 51%).

Part c. preparation of 1- (3-tert-butyl-4-methoxy-5- (1- (methylsulfonyl) indolin-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of example C (58mg, 0.145mmol) and the product of part B (56.2mg, 0.174mmol) were subjected to the conditions described in example 42, part C to give the title compound as a colourless solid (12mg, 18%).¹H NMR(300MHz，DMSO-d₆)：δ11.40(d，J＝1.84Hz，1H)7.76(d，J＝7.72Hz，1H)7.53-7.67(m，1H)7.45(s，1H)7.32-7.41(m，2H)7.23(dd，J＝13.60，2.57Hz，2H)5.63(dd，J＝8.09，2.21Hz，1H)3.99(t，J＝8.46Hz，2H)3.29(s，3H)3.18(t，J＝8.46Hz，2H)3.04(s，3H)。

EXAMPLE 68 preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinoxalin-2-yl) methanesulfonamide (Compound IB-L0-2.26).

Part a. preparation of N- (4-bromo-2-nitrophenyl) -3-oxobutanamide.

A solution of diketene (0.32ml, 4.15mmol) in toluene (2ml) was added to a solution of 4-bromo-2-nitroaniline (900mg, 4.15mmol) in toluene (7ml) at 80 ℃ and the solution was heated at reflux for 5 h. A solution of triethylamine (0.58ml, 4.15mmol) in toluene (2ml) was added and the reflux continued for 30 min. The cooled solution was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with 2: 1 hexanes/EtOAc to give the title compound as a yellow solid (920mg, 74%).

Part B. preparation of 6-bromoquinoxalin-2 (1H) -one.

To sodium hydroxide (337mg, 8.4mmol) in H₂To a solution of O (2.1ml) was added the product of part A (423mg, 1.4mmol) and stirring was continued at 65 ℃ for 1 h. Cooling solution H₂O (4ml) was diluted, sodium borohydride (31.9mg, 0.84mmol) was added and stirring continued at room temperature for 1.5 h. Ice was added to the solution and 6N HCl was added dropwise until it became acidic. The resulting solid was collected by filtration and washed with H ₂O wash, and dry in a vacuum oven to give the title compound (273mg, 86%).

Part C. preparation of 6-bromo-2-chloroquinoxaline.

To a flask containing phosphorus oxychloride (3.4ml, 36.5mmol) was added the product of part B (255mg, 1.1mmol) and the solution was heated at 60 ℃ overnight. The solution was cooled to room temperature, poured onto ice, and the resulting solid was collected by filtration to give the title compound (239mg, 87%).

Part D. preparation of 6-bromo-N- (4-methoxybenzyl) quinoxalin-2-amine.

To a solution of the product of part C (2.8g, 11.5mmol) in ethanol (58ml) was added (4-methoxyphenyl) methylamine (7.5ml, 57.5mmol) and the solution was stirred at room temperature for 1 h. The solvent was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with 20% EtOAc in hexanes to give the title compound (1.97g, 50%).

Part E. preparation of N- (4-methoxybenzyl) -6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoxalin-2-amine.

The product of part D (500mg, 1.45mmol) was subjected to the conditions of example 42, part B, to give the title compound (378mg, 66%).

Part F. preparation of 1- (3-tert-butyl-4-methoxy-5- (2- (4-methoxybenzylamino) quinoxalin-6-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione.

The product of part E (133mg, 0.34mmol) was subjected to the conditions of example 42, part C, to give the title compound (125mg, 82%).

Part G. preparation of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinoxalin-2-yl) methanesulfonamide.

To the product of part F (87mg, 0.16mmol) in CH₂Cl₂(1.6ml) and H₂DDQ (40.4mg, 0.18mmol) was added to a solution of O (0.07ml) and stirred vigorously at room temperature for 1 h. The solution was filtered through Celite and the dark solid was collected on Celite and dissolved in 5ml CH₃In OH. The methanol solution was filtered, the solvent removed in vacuo and the crude intermediate dissolved in pyridine (0.6 ml). Methanesulfonyl chloride (11. mu.l, 0.14mmol) was added and the solution was heated at 60 ℃ overnight. The cooled solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography using 2% CH₃OH/CHCl₃Elution gave the title compound (7.7mg, 12%).¹H NMR(300MHz，CDCl₃)δ8.42(s，1H)8.29(s，1H)8.13(s，1H)7.88(d，1H)7.54(s，1H)7.19-7.43(m， 4H)5.83(dd，J＝7.91，2.39Hz，1H)3.32(s，3H)3.27(s，3H)1.46(s，9H)。

EXAMPLE 69 preparation of N- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methanesulfonamide (compound IB-L0-2.44).

Part a. preparation of 5-bromo-2, 3-dihydro-1H-inden-1-ol.

A suspension of 5-bromo-2, 3-dihydro-1H-inden-1-one (2.07g, 9.81mmol) in ethanol (49mL) was treated once with sodium borohydride (186mg, 4.90 mmol). After a few minutes, the solution warmed up slightly and all solids dissolved. After stirring at room temperature for 1h, the mixture was concentrated in vacuo to remove ethanol. The resulting colloid was partitioned between ethyl acetate and water. The organic layer was extracted with saturated sodium bicarbonate solution (2 ×) and saturated sodium chloride solution. Drying (Na) ₂SO₄) Concentration in vacuo gave the title compound (3.05g, 98%) as a colourless oil which was crystallised by suction under high vacuum overnight.

Part B, preparation of 1-azido-5-bromo-2, 3-dihydro-1H-indene.

A solution of the product of part A (1.01g, 4.73mmol) in toluene (8.1mL) was treated with diphenylphosphorylazide (1.23mL, 1.56g, 5.67mmol) and then cooled to 0 ℃. The solution was treated with DBU (855. mu.L, 863mg, 5.67mmol) dropwise, then stirred at 0 ℃ for 2h, then warmed to room temperature for 48 h. The mixture was diluted with ethyl acetate, extracted with water and 1M citric acid solution, and then extracted with saturated sodium chloride solution. Drying (Na)₂SO₄) Concentrated in vacuo to provide a brown oil, which is purified by flash chromatography, eluting with 5-50% ethyl acetate in hexane. These procedures provided the title compound (889mg, 79%) as a pale yellow oil.

Part c. preparation of 5-bromo-2, 3-dihydro-1H-inden-1-amine.

A solution of the product of part B (200mg, 0.84mmol) in THF (0.88ml) at-15 deg.C was added dropwise to a solution of 1M lithium aluminum hydride (0.84ml, 0.84mmol) and the solution warmed to room temperature and stirred overnight. The solution was cooled to-10 ℃ and 4: 1 THF: H was added dropwise₂O (0.5 ml). The solution is at room temperatureStirring was continued for 4h, filtration through Celite and the filtrate was concentrated in vacuo to give the title compound (151mg, 85%).

Part d. preparation of N- (5-bromo-2, 3-dihydro-1H-inden-1-yl) methanesulfonamide.

To a solution of the product of part C (150mg, 0.71mmol) in pyridine (3.5ml) was added methanesulfonyl chloride (61. mu.l, 0.78mmol) and the solution was stirred at room temperature overnight. The solution was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with 20% EtOAc in hexanes to give the title compound (111mg, 54%).

Part e. preparation of N- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methanesulfonamide.

The product of part D (109mg, 0.38mmol) was subjected to the conditions of example 42, part B and part C to give the title compound (39mg, 60%).¹H NMR(300MHz，DMSO-d₆)δ11.39(d，J＝1.84Hz，1H)7.77(d，J＝7.72Hz，1H)7.58(d，J＝8.82Hz，1H)7.39-7.48(m，3H)7.27(d，J＝2.57Hz，1H)7.19-7.23(m，1H)5.63(dd，J＝8.09，2.21Hz，1H)4.86(q，J＝7.97Hz，1H)3.27(s，3H)3.04(s，3H)2.90-3.01(m，1H)2.71-2.90(m，1H)2.52-2.62(m，1H)1.85-1.98(m，1H)1.40(s，9H)。

EXAMPLE 70 preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.17).

Part a. preparation of (E) -5-bromo-1- (methoxymethylene) -2, 3-dihydro-1H-indene.

To-20 deg.C (methoxymethyl) triphenylphosphonium chloride (39.7g, 11)6mmol) of potassium tert-butoxide (95ml, 95mmol) were added dropwise to a suspension in THF (210ml) and the solution was stirred at-20 ℃ for 20 min. To this solution was added dropwise a solution of 5-bromo-2, 3-dihydro-1H-inden-1-one (10.0g, 47.4mmol) in THF (230ml), stirring at-20 deg.C for an additional 30min, then warmed to room temperature and stirred for 2H. The solution was filtered through Celite and the filtrate was concentrated in vacuo to give the crude product which was purified by chromatography on a silica gel column using CH ₂Cl₂Hexane elution gave the title compound (10.56g, 93%).

Part b. preparation of 5-bromo-2, 3-dihydro-1H-indene-1-carbaldehyde.

To the product of part A at-78 deg.C (1.44g, 6.0mmol) in CH₂Cl₂(30ml) solution was added dropwise with 1M boron tribromide CH₂Cl₂(13.8ml, 13.8mmol) and stirring at-78 deg.C was continued for 4 h. The solution was poured into an ice-saturated sodium bicarbonate mixture and stirred vigorously. The layers were separated and the aqueous layer was treated with CH₂Cl₂(2X) extraction, combine organic extracts and dry (Na)₂SO₄) Concentration in vacuo afforded the crude product, which was purified by silica gel column chromatography eluting with 10% EtOAc in hexanes to afford the title compound (604mg, 45%).

Part c. preparation of 1- (5-bromo-2, 3-dihydro-1H-inden-1-yl) -N- (4-methoxybenzyl) -methylamine.

To the product of part B (300mg, 1.3mmol) in CH₃To a solution of OH (18.5ml) was added 4-methoxybenzylamine (0.17ml, 1.3mmol) and decaborane (49mg, 0.4mmol), stirring was continued at room temperature for 1h, the solvent was concentrated in vacuo and the crude product was purified by column chromatography on silica gel with 3% CH₃OH/CHCl₃Elution gave the title compound (264mg, 57%).

Part d. preparation of N- ((5-bromo-2, 3-dihydro-1H-inden-1-yl) methyl) -N- (4-methoxy-benzyl) methanesulfonamide.

To the product of part C (88mg, 0.25mmol) in CH ₂Cl₂To a solution (1.0ml) were added triethylamine (39. mu.l, 0.28mmol) and methanesulfonyl chloride (22. mu.l, 0.28mmol) at room temperatureStirring was continued for 1h, the solvent was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with EtOAc/hexanes to give the title compound (55mg, 51%).

Part e. preparation of N- (4-methoxybenzyl) -N- ((5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide.

The product of part D (1.15g, 2.71mmol) was subjected to the conditions of example 42, part B, to give the title compound (840mg, 66%).

Part f. preparation of N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide.

The product of part E (840mg, 2.1mmol) was subjected to the conditions of example 42, part C, and the isolated material (1.28g, 2.07mmol) was dissolved in CH₂Cl₂To (10ml) was added trifluoroacetic acid (10ml) slowly. After stirring at room temperature for 1h, the solvent was concentrated in vacuo and the crude product was suspended in 10% NaHCO₃In (C) with CH₂Cl₂(3X) extraction, combine organic extracts and dry (Na)₂SO₄) The solvent was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography using 2% CH ₃OH/CHCl₃Elution gave the title compound (0.84g, 81%).¹H NMR(300MHz，DMSO-d₆)δ 11.39(s，1H)7.77(d，J＝8.09Hz，1H)7.29-7.59(m，3H)7.25(d，J＝2.94Hz，1H)7.10-7.22(m，2H)5.63(dd，J＝7.72，1.84Hz，1H)3.93(s，3H)3.26(s，2H)3.23-3.40(m，1H)2.89(s，3H)2.71-3.09(m，2H)2.14-2.32(m，1H)1.75-1.95(m，1H)1.40(s，9H)。

EXAMPLE 71 preparation of 5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -N- (methylsulfonyl) -2, 3-dihydro-1H-indene-1-carboxamide (Compound IB-L0-2.34).

Part a. preparation of 5-bromo-2, 3-dihydro-1H-indene-1-carboxylic acid.

To the product of example 70, part B (300mg, 1.3mmol) and 2-methyl-2-pentene (8ml) in tert-butanol (32ml) was added sodium hypochlorite (1.36g, 0.12mmol) containing sodium dihydrogen phosphate (1.07g, 8.9mmol) and H₂O (12ml) solution, the mixture was stirred vigorously at room temperature for 20 min. The solvent is concentrated in vacuo and the residue is taken up in H₂Dilute O, extract with EtOAc (3 ×), combine extracts, and dry (Na)₂SO₄) Concentration in vacuo afforded the title compound (180mg, 56%).

Part b. preparation of 5-bromo-N- (methylsulfonyl) -2, 3-dihydro-1H-indene-1-carboxamide.

To the product of part A (100mg, 0.42mmol) in CH₂Cl₂To the solution (1.7ml) carbonyl diimidazole (67.3mg, 0.42mmol) was added and the reaction stirred at room temperature for 2 h. Methanesulfonamide (39.5mg, 0.42mmol) and DBU (62.5mg, 0.42mmol) were added and stirring continued at room temperature for 2 h. CH for solution₂Cl₂Diluted, washed with 1N HCl, brine and dried (Na) ₂SO₄) Concentrated in vacuo and the crude product purified by column chromatography on silica eluting with 20% EtOAc in hexanes to give the title compound (121mg, 92%).

Part c. preparation of N- (methylsulfonyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-indene-1-carboxamide.

The product of part B (159mg, 0.5mmol) was subjected to the conditions of example 42, part B, to give the title compound (144mg, 79%).

Part d. preparation of 5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -N- (methylsulfonyl) -2, 3-dihydro-1H-indene-1-carboxamide.

The product of part C (134mg, 0.34mmol) was subjected to the conditions of example 42, part C, to give the title compound (14mg, 8%).¹H NMR(300MHz，CDCl₃)δ8.11(m，1H)7.08-7.57(m，7H)5.80(dd，J＝7.91，2.39Hz，1H)4.07(dd，J＝9.01，6.07Hz，1H)3.33(s，3H)3.08(s，3H)2.91-3.22(m，1H)2.35-2.74(m，1H)1.44(s，9H)1.17-1.34(m，1H)0.60-1.00(m，1H)。

EXAMPLE 72 preparation of 1- (3- (2-aminobenzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxy-phenyl) pyrimidine-2, 4(1H, 3H) -dione (Compound IB-L0-2.39).

Using the procedure described for the preparation of example 53, with 5-bromo [ d ]]Thiazol-2-amines instead of 6-bromobenzo [ d]Thiazol-2-amine to prepare the title compound.¹H NMR(300MHz，DMSO-d₆)δ11.40(d，J＝1.84Hz，1H)8.40(s，2H)7.84(d，J＝8.09Hz，1H)7.78(d，J＝7.72Hz，1H)7.54(d，J＝1.47Hz，1H)7.27-7.32(m，3H)5.64(dd，J＝8.09，2.21Hz，1H)3.27(s，3H)1.41(s，9H)。

EXAMPLE 73 preparation of N- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide (compound IB-L0-2.29).

To the product of example 45, part D (20mg, 0.038mmol) in 1: 1 benzene: MeOH (0.6ml) was added platinum (IV) oxide (1 mg). The resulting mixture was at 1 atmosphere H₂Stirring the mixture at room temperature for 1 hour,then, filtered through Celite and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using CHCl₃3% MeOH as eluent to give the title compound as a solid (14mg, 70%).¹H NMR(300MHz，DMSO-d₆)δ11.39(s，1H)7.77(d，J＝7.72Hz，1H)7.58(d，J＝8.09Hz，1H)7.28-7.38(m，2H)7.21-7.26(m，2H)7.07(s，1H)5.63(d，J＝7.72Hz，1H)3.61(dd，J＝8.64，5.33Hz，1H)3.25(s，3H)3.00(s，3H)2.75-2.98(m，2H)1.97-2.21(m，2H)1.40(s，9H)1.24(d，J＝8.46Hz，6H)。

EXAMPLE 74 preparation of (S) -N- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide (Compound IB-L0-2.22).

The product of example 73 (10mg) was subjected to chiral chromatography (Chiralpak AD-H column; eluted with 1: 32-PrOH: hexane (0.1% TFA)). The earlier eluted fractions were separated to give the title compound (4.4 mg).¹H NMR was the same as the product of example 73.

EXAMPLE 75 preparation of (R) -N- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide (Compound IB-L0-2.37).

The product of example 73 (10mg) was subjected to chiral chromatography (Chiralpak AD-H column; eluted with 1: 32-PrOH: hexane (0.1% TFA)). Separating later To give the title compound (4.2 mg).¹H NMR was the same as the product of example 73.

EXAMPLE 76 preparation of (S) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.9).

The product of example 70, part F (20mg) was subjected to chiral chromatography (Chiralpak AD-H column; eluted with 1: 42-PrOH: hexane (0.1% TFA)). The earlier eluted fractions were separated to give the title compound (5.3 mg).¹H NMR was the same as example 70, part F product.

EXAMPLE 77 preparation of (R) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.15).

The product of example 70, part F (20mg) was subjected to chiral chromatography (Chiralpak AD-H column; eluted with 1: 42-PrOH: hexane (0.1% TFA)). The later eluting component was isolated to give the title compound (5.7 mg).¹H NMR was the same as example 70, part F product.

EXAMPLE 78 preparation of (S) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.20).

The product of example 61, part H was subjected to the conditions of example 74 to give the title compound.¹H NMR was the same as example 61, part H product.

EXAMPLE 79 preparation of (R) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide (compound IB-L0-2.10).

The product of example 61, part H was subjected to the conditions of example 74 to give the title compound.¹H NMR was the same as example 61, part H product.

EXAMPLE 80 preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3-tert-pentylphenyl) naphthalen-2-yl) methanesulfonamide (Compound IB-L0-2.52).

Part a. preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione.

Following the procedure of example C, part a, part B and part C, 2-tert-amylphenol (5.0g, 30mmol) was reacted to provide the title product as a colorless solid (6.7g, 56%, 3 steps total yield).

Part b. preparation of N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3-tert-pentylphenyl) naphthalen-2-yl) methanesulfonamide.

The product of part a (100mg, 0.241mmol), the product of example 2A, part B (92mg, 0.266mmol), sodium carbonate (38.4mg, 0.362mmol) and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (9.9mg, 0.012mmol) were dissolved in a solvent mixture of toluene (4mL) and ethanol (4mL), sparged with nitrogen for 10min, and the mixture was then heated at 85 ℃ for 18 h. Then, CH was added to the solution ₂Cl₂(20mL), then 1N aqueous HCl (10mL) was added, the organic layer was separated, and 3-mercaptopropyl silica gel (100mg) and magnesium sulfate were added. Concentrating the solution, purifying by silica gel column chromatography using CH₂Cl₂3% MeOH as eluent provided the title compound as a colorless solid (71mg, 58%).¹H NMR(300MHz，DMSO-d₆)：δ11.41(s，1H)，10.04(s，1H)，8.03(s，1H)，7.95(t，J＝8.7Hz，2H)，7.79(d，J＝7.7Hz，1H)，7.73(d，J＝1.8Hz，1H)，7.69(dd，J＝8.8，1.6Hz，1H)，7.42(dd，J＝8.8，2.2Hz，1H)，7.37(d，J＝2.6Hz，1H)，7.25(d，J＝2.6Hz，1H)，5.65(dd，J＝8.1，1.6Hz，1H)，3.22(s，3H)，3.08(s，3H)，1.84(m，2H)，1.38(s，6H)，0.73(t，J＝7.5Hz，3H)。

EXAMPLE 81 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) -N-methylmethanesulfonamide (compound IB-L0-2.16).

Part a. preparation of N-methyl-N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-inden-3-yl) methyl) methanesulfonamide.

To a solution of the product of example 49, part E (210mg, 0.60mmol) in anhydrous THF (5ml) was added a 1.0M solution of lithium bis (trimethylsilyl) amide in toluene (0.60ml, 0.60mmol) and the resulting mixture was stirred at room temperature for 5 min. Methyl iodide (0.075ml, 1.20mmol) was added and the mixture stirred at room temperature for 2h and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of ethyl acetate in hexane (10% to 25%) to give the title compound as a solid (125mg, 57%).

Part b. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) -N-methylmethanesulfonamide.

A mixture of the product from example C (60.0mg, 0.15mmol), the product of part A (54.5mg, 0.15mmol), potassium phosphate (66.9mg, 0.315mmol), PA-Ph (CAS97739-46-3, 1.32mg, 4.5. mu. mol) and tris (dibenzylideneacetone) dipalladium (0) (1.37mg, 1.5. mu. mol) in tetrahydrofuran (3.0ml) and water (1.0ml) was flushed with nitrogen for 30 min. The mixture was stirred at 50 ℃ for 2h, then partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered through Celite, and concentrated in vacuo. The crude product was purified by column chromatography on C-18 reverse phase silica gel using a solvent gradient of 10-100% acetonitrile in water (0.1% TFA) to give the title compound as a solid (19mg, 24%).¹H NMR(300MHz，DMSO-d₆)δ11.40(d，J＝1.84Hz，1H)7.78(d，J＝7.72Hz，1H)7.65(m，2H)7.49(dd，J＝7.72，1.47Hz，1H)7.26(m，2.57Hz，2H)6.63(s，1H)5.64(dd，J＝7.72，2.21Hz，1H)4.26(s，2H)3.51(s，2H)3.26(s，3H)3.01(s，3H)2.72(s，3H)1.41(s，9H)。

EXAMPLE 82 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-2-yl) methyl) methanesulfonamide (compound IB-L0-2.40).

Part a. preparation of 6-bromobenzo [ b ] thiophene-2-carboxylic acid ethyl ester.

To a solution of 4-bromo-2-fluorobenzaldehyde (1.02g, 4.83mmol) in DMSO (4mL) was added ethyl 2-mercaptoacetate (0.58mL, 5.31mmol) followed by Et₃N (1.35mL, 9.65mmol), the mixture was heated at 80 ℃ for 3 h. The resulting dark mixture was poured into water (50mL) and extracted with EtOAc (2X 50 mL). The combined organic extracts were washed with 10% NaCl and anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo afforded the title compound as a pale yellow waxy solid (1.29g, 94%).

Part b preparation of (6-bromobenzo [ b ] thiophen-2-yl) methanol.

To the product of part A (0.82g, 2.88mmol) in Et at 0 deg.C₂Et 1M lithium aluminum hydride in O (20mL) solution₂O (3.16mL, 3.16mmol) solution and the resulting slurry was stirred at 5-10 deg.C for 1 h. 0.3mL of H for the slurry₂O, 0.3mL of 15% aqueous NaOH solution, 0.7mLH₂Treatment with O, stirring for 30min, filtration, and concentration in vacuo afforded the title compound as a colorless solid (0.58g, 83%).

Part c. preparation of 6-bromo-2- (bromomethyl) benzo [ b ] thiophene.

The product of part B (85mg, 0.35mmol), N-bromosuccinimide (74mg, 0.413mmol) and triphenylphosphine (106mg, 0.403mmol) in CH₂Cl₂(2mL) the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 50mL CH ₂Cl₂Diluting with water and 10% NaHCO₃And 10% NaCl, over anhydrous MgSO₄Drying, filtering and vacuum concentrating. The residue was purified by column chromatography on silica gel using 9: 1 hexaneEtOAc elution afforded the title compound as a white solid (96mg, 89%).

Part d. preparation of N- (4-methoxybenzyl) methanesulfonamide.

To (4-methoxyphenyl) methylamine (1.317g, 9.60mmol) in CH₂Cl₂To the solution (10mL) was added methanesulfonyl chloride (0.34mL, 4.36mmol) dropwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 50mL CH₂Cl₂Diluting with 1N H₃PO₄10% NaCl, over anhydrous MgSO₄Drying, filtration, and concentration in vacuo afforded the title compound as a white solid (0.84g, 89%).

Part e. preparation of N- ((6-bromobenzo [ b ] thiophen-2-yl) methyl) -N- (4-methoxybenzyl) -methanesulfonamide.

A solution of the product of part D (0.223g, 1.037mmol) in EtOH (2mL) and 1.0M NaOH (1.1mL, 1.1mmol) was added to a slurry of the product of part C (0.317g, 1.037mmol) in EtOH (4 mL). The resulting slurry was heated under reflux for 1h, then concentrated in vacuo to give a paste solid. The residue was partitioned between 40mL water and 40mL EtOAc. 1N H for organic layer₃PO₄、10％NaHCO₃Washed with 10% NaCl and dried over Na ₂SO₄Dried, filtered and concentrated in vacuo to leave a yellow oil. The crude product was purified by silica gel column chromatography using CH₂Cl₂Elution afforded the title compound as a colorless solid (0.15g, 33%).

Part f. preparation of N- (4-methoxybenzyl) -N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ b ] thiophen-2-yl) methyl) methanesulfonamide.

The product of part E (0.15g, 0.34mmol) was subjected to the conditions used to prepare example 42, part B, to give the title compound as a colourless solid (0.121g, 73%).

Part g. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-2-yl) methyl) -N- (4-methoxybenzyl) methanesulfonamide.

The product of part F (24mg, 0.049mmol) was subjected to the conditions used to prepare example 42, part C, to give the title compound as a colorless solid (20mg, 65%).

Preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-2-yl) methyl) methanesulfonamide.

The product of fraction G (14mg, 0.022mmol) was washed with CH₂Cl₂(0.3mL) and TFA (0.3mL) solutions were stirred at room temperature for 4h, then concentrated in vacuo. The residue was in 10mL CH ₂Cl₂And 2mL of 10% NaHCO₃The aqueous solution was partitioned between and the organic layer was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 99: 1CH₂Cl₂MeOH elution afforded the title compound as a colorless solid (5mg, 44%).¹H NMR(300MHz，DMSO-d₆)δ11.40(s，1H)8.09(s，1H)7.82-7.97(m，3H)7.79(d，J＝7.72Hz，1H)7.47-7.63(m，1H)7.40(s，1H)7.26-7.34(m，1H)5.64(d，J＝7.72Hz，1H)4.48(d，J＝5.88Hz，2H)3.23(s，3H)2.95(s，3H)1.41(s，9H)。

EXAMPLE 83 preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) -N-methylmethanesulfonamide (compound IB-L0-2.21).

Part a. preparation of N- ((6-bromobenzo [ b ] thiophen-3-yl) methyl) -N-methylmethanesulfonamide.

The product of example 46, part D (0.100g, 0.382mmol), N-methylmethanesulfonamide (45.9mg, 0.421mmol) and potassium carbonate (0.127g, 0.918mmol) in N, N-dimethylacetamide(5mL) the mixture was stirred at 80 ℃ for 11h, cooled to room temperature, partitioned between ether and water (3X), and MgSO₄Drying, filtration and concentration in vacuo gave the title compound as a colorless waxy solid (0.128g, quantitative).

Part b. preparation of N-methyl-N- ((6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide.

The product of part a (0.128g, 0.382mmol) was subjected to the conditions used to prepare example 42, part B, to give the title compound as a colorless crystalline solid (0.120g, 82%).

Part c. preparation of N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) -N-methylmethanesulfonamide.

The product of part B (50.6mg, 0.133mmol) was subjected to the conditions used to prepare example 49, part F, to give the title compound as a colorless solid (61.5mg, 88%).¹H NMR(300MHz，DMSO-d₆)δ11.41(s，1H)8.17(d，J＝1.47Hz，1H)8.09(d，J＝8.09Hz，1H)7.74-7.85(m，2H)7.63(dd，J＝8.46，1.47Hz，1H)7.29-7.36(m，2H)5.65(d，J＝7.72Hz，1H)4.52(s，2H)3.24(s，3H)3.03(s，3H)2.70(s，3H)1.42(s，9H)。

The following compounds were prepared using the above discussion:

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-benzo [ d]Imidazol-5-yl) -N- (methylsulfonyl) methanesulfonamide (compound IA-L0-2.10).¹H NMR(300MHz，DMSO-d₆)δppm 1.45(s，9H)2.73(t，J＝6.62Hz，2H)3.48(s，3H)3.56(s，6H)3.83(t，J＝6.80Hz，2H)4.05(s，1H)7.38(dd，J＝8.46，1.84Hz，1H)7.46(d，J＝2.57Hz，1H)7.71(d，J＝8.46Hz，1H)7.76(d，J＝2.57Hz，1H)7.82(d，J＝1.84Hz，1H)10.41(s，1H)

N- ((6- (3-tert-butyl-2-chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidine-1: (1))2H) -yl) phenyl) benzo [ b]Thien-3-yl) methyl) methanesulfonamide (compound IB-L0-2.35).¹H NMR(300MHz，DMSO-d₆)δppm 1.52(s，9H)2.95(s，3H)4.44(d，J＝5.88Hz，2H)5.68(d，J＝8.09Hz，1H)7.40(d，J＝2.57Hz，1H)7.46(dd，J＝8.09，1.47Hz，1H)7.56(d，J＝2.57Hz，1H)7.62(t，J＝6.07Hz，1H)7.72(s，1H)7.83(d，J＝8.09Hz，1H)8.01(m，2H)11.46(s，1H)。

1- (3-tert-butyl-5- (2-chlorobenzo [ d ]]Thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione (compound IB-L0-2.38).¹H NMR(300MHz，DMSO-d₆) δppm 1.41(s，9H)3.24(s，3H)5.65(dd，J＝8.09，2.21Hz，1H)7.34(s，2H)7.73(dd，J＝8.64，1.65Hz，1H)7.79(d，J＝8.09Hz，1H)8.07(d，J＝8.46Hz，1H)8.30(d，J＝1.84Hz，1H)11.42(d，J＝1.84Hz，1H)

N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinolin-6-yl) methanesulfonamide (compound IB-L0-2.48).

1- (3-tert-butyl-4-methoxy-5- (1-oxo-2, 3-dihydro-1H-inden-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione (compound IB-L0-2.50).

N, N '- (6, 6' - (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-1, 3-phenylene) bis (naphthalene-6, 2-diyl)) dimethanesulfonamide (compound IB-L0-2.76).¹H NMR(300MHz，DMSO-d₆)δppm 3.08(s，6H)3.13(s，3H)5.72(d，J＝8.18Hz，1H)7.43(dd，J＝8.46，1.84Hz，2H)7.59(s，2H)7.79(m，4H)7.96(m，5H)8.14(s，2H)10.05(s，2H)11.48(s，1H)。

HCV polymerase inhibition assay

At room temperature with 20mM Tris-Cl pH 7.4, 2mM MnCl₂1mM dithiothreitol, 1mM ethylenediaminetetraacetic acid (EDTA), 60-125. mu.M GTP and 20-50 nM Δ 21NS5B (HCV Strain 1B (BK, Genbank accession M58335, or H77, Genbank accession AF011751)) culture crossover inhibitorsTwo-fold serial dilutions of the IC50 of the formulation (fractional inhibition assay) or a narrower range of dilutions (tight binding assay) were used for 15 min. By adding 20. mu.M CTP, 20. mu.M ATP, 1. mu.M³The reaction was initiated with H-UTP (10mCi/umol), 5nM template RNA and 0.1U/. mu.l RNase inhibitor (RNase, Promega) and was carried out at room temperature for 2-4H. The reaction volume was 50. mu.l. The reaction was stopped by adding 1 volume of 4mM spermine in 10mM Tris-Cl pH 8.0, 1mM EDTA. After incubation at room temperature for at least 15min, the precipitated RNA was captured by filtration through a 96-well GF/B filter (Millipore). The filter plates were washed three times with 200. mu.l each of 2mM spermine, 10mM Tris-Cl pH 8.0, 1mM EDTA and twice with ethanol. After air drying, 30 μ l Microscint 20 scintillation cocktail (Packard) was added to each well and the remaining cpm (counts per minute) was determined by scintillation counting. The minimum and maximum values of the curve were determined using the uncontrolled control and the fully inhibited control samples, and the IC was calculated by a nonlinear regression equation of the two variables ₅₀The value is obtained. For the expression of IC in the fractional inhibition analysis₅₀Those compounds with values less than 0.005 μ M were subjected to tight binding assays to more accurately measure IC₅₀The value is obtained. The remaining cpm was plotted against inhibitor concentration and fitted to equation 1 using non-linear regression (ref 1) to obtain the IC₅₀The value:

retained cpm ═ a [ sqrt { (IC)₅₀+I_t-E_t)^2+4*IC₅₀*E_t}-(IC₅₀+I_t-E_t)](equation 1)

Wherein a is Vmax [ S ]/2(Km + [ S ]); it is the total inhibitor concentration, and Et is the total active concentration of the enzyme.

Reference, Morrison, j.f. and s.r.stone, 1985. Methods of studying and analyzing enzyme inhibition by slow and tight binding of inhibitors. Compositions mol.cell.biophysis.2: 347-368.

The template RNA sequences used were: 5'-GGGCGAAUUG GGCCCUCUAGAUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCAGAAUUCGCCC UUGGUGGCUC CAUCUUAGCC CUAGUCACGGCUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAGUGCUGAUACU GGCCUCUCUG CAGAUCAAGUC-3' are provided.

The compounds of the present invention inhibit HCV polymerase 1A and/or 1B when tested using the methods described above. The following is illustrated in the table below: a- -IC₅₀≤0.01μM；B--0.1μM≥IC₅₀＞0.01μM；C--1μM≥IC₅₀More than 0.1 μ M; and D- -IC₅₀More than 1 mu M; ND-was not determined.

Watch IC ₅₀

Compound (I)	1a	1b	Compound (I)	1a	1b
									IA-L0-2.1	C	C
IA-L0-2.2	B	B	IA-L0-2.3	C	C
						IA-L0-2.4	B	B	IA-L0-2.5	C	C
IA-L0-2.6	C	C	IA-L0-2.7	C	C
						IA-L0-2.8	B	B	IA-L0-2.9	A	A
IA-L0-2.10	D	D	IB-L0-2.1	C	C
						IB-L0-2.2	C	C	IB-L0-2.3	A	A
IB-L0-2.4	A	A	IB-L0-2.5	B	B
						IB-L0-2.6	B	B	IB-L0-2.7	B	B
IB-L0-2.8	B	B	IB-L0-2.9	A	A
						IB-L0-2.10	A	B	IB-L0-2.11	A	A
IB-L0-2.12	A	B	IB-L0-2.13	A	B
						IB-L0-2.14	A	A	IB-L0-2.15	A	B
IB-L0-2.16	A	B	IB-L0-2.17	A	B
						IB-L0-2.18	A	B	IB-L0-2.19	A	B

IB-L0-2.20	A	B	IB-L0-2.21	B	B
						IB-L0-2.22	B	B	IB-L0-2.23	B	A
IB-L0-2.24	B	B	IB-L0-2.25	B	B
						IB-L0-2.26	B	B	IB-L0-2.27	B	B
IB-L0-2.28	B	B	IB-L0-2.29	B	B
						IB-L0-2.30	B	B	IB-L0-2.31	B	B
IB-L0-2.32	B	B	IB-L0-2.33	B	B
						IB-L0-2.34	B	B	IB-L0-2.35	B	B
IB-L0-2.36	B	C	IB-L0-2.37	C	C
						IB-L0-2.38	C	B	IB-L0-2.39	C	C
IB-L0-2.40	C	C	IB-L0-2.41	C	C
						IB-L0-2.42	C	C	IB-L0-2.43	C	C
IB-L0-2.44	C	C	IB-L0-2.45	C	C
						IB-L0-2.46	C	C	IB-L0-2.47	D	D
IB-L0-2.48	D	D	IB-L0-2.49	D	D
						IB-L0-2.50	B	B	IB-L0-2.51	A	B
IB-L0-2.52	A	B	IB-L0-2.53	A	B
						IB-L0-2.54	A	B	IB-L0-2.55	A	B
IB-L0-2.56	A	B	IB-L0-2.57	A	B
						IB-L0-2.58	A	B	IB-L0-2.59	A	B
IB-L0-2.60	A	B	IB-L0-2.61	A	B
						IB-L0-2.62	B	B	IB-L0-2.63	B	B
IB-L0-2.64	B	B	IB-L0-2.65	B	A
						IB-L0-2.66	B	B	IB-L0-2.67	B	B
IB-L0-2.68	B	B	IB-L0-2.69	B	B
						IB-L0-2.70	B	C	IB-L0-2.71	C	C
IB-L0-2.72	C	C	IB-L0-2.73	C	C
						IB-L0-2.74	C	C	IB-L0-2.75	C	D
IB-L0-2.76	C	D	IB-L0-2.77	D	D
						IB-L0-2.78	D	D	IB-L0-2.79	B	B

HCV polymerase replication assay

Two stable subgenomic replicon cell lines were used in cell culture for compound characterization: one cell line was derived from genotype 1a-H77 and one cell line was derived from genotype 1b-Con1 (obtained from Apath, LLC, St. Louis, Mo.). All replicon constructs were bicistronic Subgenomic replicons, similar to those of Bartenschlager and collaborators (Lohmann et al, Replication of Subgenomic Hepatitis C RNAs in a Heatotema Cell Line, SCIENCE 285: 110-3 (1999)). The Genotype 1a replicon construct contains the NS3-NS5B coding region derived from the H77 strain of HCV (1a-H77) (Blight et al, efficiency replication of Hepatitis C viruses Genotype 1a RNAs in Cell Culture, J.VIROL.77: 3181-90 (2003)). The replicon also had a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions were isolated by FMDV 2a protease, the first cistron comprising the bicistronic replicon construct and the second cistron containing the NS3-NS5B coding region with the addition of the adaptive mutations E1202G, K1691R, K2040R and S2204I. The 1b-Con1 replicon construct was identical to the 1a-H77 replicon, except that the NS3-NS5B coding region was derived from the 1b-Con1 strain and the adaptive mutations were E1202G, T1280I and S2204I. The replicon cell lines were maintained in Dulbecco's Modified Eagles Medium (DMEM) containing 10% (v/v) Fetal Bovine Serum (FBS), 100IU/ml penicillin, 100mg/ml streptomycin (Invitrogen) and 200mg/ml G418 (Invitrogen).

The inhibitory effect of a compound on HCV replication was determined by measuring the activity of a luciferase reporter gene. Briefly, replicon-containing cells were seeded into 100 μ l of DMEM containing 5% FBS in 96-well plates at a density of 5000 cells/well. After 16-24 hours, compounds were diluted in dimethyl sulfoxide (DMSO) to generate a series of 200-fold stock solutions diluted 8.5-log. Then, the dilution series were further diluted 100-fold in a medium containing 5% FBS. The inhibitor-containing medium was added to an overnight cell culture plate already containing 100 μ l of DMEM containing 5% FBS. In assays measuring inhibitory activity in the presence of human plasma, media from overnight cell culture plates was replaced with DMEM containing 40% human plasma and 5% FBS. Cells were cultured in a tissue culture incubator for 3 days, and then lysed for RNA extraction. For luciferase assay, 30. mu.l of passive lysis buffer (Promega) was added to each well, and then the plate was incubated for 15min with shaking to lyse the cells. Luciferin solution (50-100 ul, Promega) was added to each well and luciferase activity was measured using a Victor II luminometer (Perkin-Elmer). Percent inhibition of HCV RNA replication was calculated for each compound concentration, using the fit Calculation of EC by nonlinear regression Curve and GraphPad Prism 4 software as 4-parameter logarithmic equation₅₀The value is obtained.

The compounds of the present invention inhibit HCV polymerase 1A and/or 1B when tested using the methods described above. The following is illustrated in the table below: a- -EC₅₀≤0.01μM；B--0.1μM≥EC₅₀＞0.01μM；C--1μM≥EC₅₀More than 0.1 μ M; and D- -EC₅₀More than 1 mu M; ND-was not determined.

Watch EC ₅₀

Compound (I)	1a	1b	Compound (I)	1a	1b
									IA-L0-2.1	D	D
IA-L0-2.2	C	B	IA-L0-2.3	C	C
						IA-L0-2.4	D	C	IA-L0-2.5	D	D
IA-L0-2.6	D	D	IA-L0-2.7	D	C
						IA-L0-2.8	C	B	IA-L0-2.9	A	A
IA-L0-2.10	ND	ND	IB-L0-2.1	D	C
						IB-L0-2.2	D	D	IB-L0-2.3	A	A
IB-L0-2.4	ND	A	IB-L0-2.5	B	A
						IB-L0-2.6	C	B	IB-L0-2.7	C	B
IB-L0-2.8	ND	B	IB-L0-2.9	A	A
						IB-L0-2.10	A	A	IB-L0-2.11	B	A
IB-L0-2.12	B	A	IB-L0-2.13	B	A
						IB-L0-2.14	C	B	IB-L0-2.15	C	B
IB-L0-2.16	C	A	IB-L0-2.17	B	A
						IB-L0-2.18	C	B	IB-L0-2.19	B	B
IB-L0-2.20	C	B	IB-L0-2.21	C	B
						IB-L0-2.22	C	B	IB-L0-2.23	C	B
IB-L0-2.24	B	B	IB-L0-2.25	C	B
						IB-L0-2.26	D	C	IB-L0-2.27	C	B
IB-L0-2.28	D	C	IB-L0-2.29	C	B
						IB-L0-2.30	C	B	IB-L0-2.31	C	B
IB-L0-2.32	C	B	IB-L0-2.33	C	C
						IB-L0-2.34	D	C	IB-L0-2.35	D	C
IB-L0-2.36	C	B	IB-L0-2.37	D	C

IB-L0-2.38	D	D	IB-L0-2.39	D	C
						IB-L0-2.40	D	C	IB-L0-2.41	C	C
IB-L0-2.42	C	C	IB-L0-2.43	D	C
						IB-L0-2.44	D	D	IB-L0-2.45	D	C
IB-L0-2.46	ND	ND	IB-L0-2.47	ND	ND
						IB-L0-2.48	ND	ND	IB-L0-2.49	ND	ND
IB-L0-2.50	C	C	IB-L0-2.51	B	A
						IB-L0-2.52	B	A	IB-L0-2.53	B	B
IB-L0-2.54	B	B	IB-L0-2.55	B	A
						IB-L0-2.56	C	A	IB-L0-2.57	C	B
IB-L0-2.58	B	A	IB-L0-2.59	C	B
						IB-L0-2.60	C	B	IB-L0-2.61	C	B
IB-L0-2.62	C	B	IB-L0-2.63	C	B
						IB-L0-2.64	C	A	IB-L0-2.65	C	B
IB-L0-2.66	C	B	IB-L0-2.67	C	B
						IB-L0-2.68	D	C	IB-L0-2.69	C	B
IB-L0-2.70	D	C	IB-L0-2.71	C	B
						IB-L0-2.72	D	C	IB-L0-2.73	C	C
IB-L0-2.74	D	C	IB-L0-2.75	D	D
						IB-L0-2.76	ND	ND	IB-L0-2.77	ND	ND
IB-L0-2.78	ND	ND	IB-L0-2.79	C	C

* * * * * * * * * * *

All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended merely to summarize the assertions made by their authors and no admission is made that any reference (or portion of any reference) is relevant prior art (or prior art at all). Applicants have the right to challenge the accuracy and pertinence of the cited references.

Claims (92)

1. A compound or salt thereof, wherein:

the compounds correspond in structure to formula I-L0:

selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond;

R¹is hydrogen;

R²is hydrogen;

R³is hydrogen;

R⁴selected from halogen, C₁-C₆Alkyl radical, C₂-C₆Alkynyl, amino, aminosulfonyl, C₁-C₆Alkylsulfonyl radical, C₃-C₁₄Carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a) amino and aminosulfonyl are optionally independently selected from C₁-C₆Alkyl and C₁-C₆One or two substituents of the alkylsulfonyl group, and

(b)C₁-C₆alkyl and C₂-C₆Alkynyl is optionally independently selected from halogen, oxo, C₁-C₆Substituted with one or more substituents of alkoxy and trimethylsilyl, and

(c)C₃-C₁₄carbocyclyl and 5-6 membered heterocyclyl are optionally independently selected from C₁-C₆Alkyl, halogen and amino, wherein:

amino optionally substituted by one or two C₁-C₆Alkyl carbonyl substitution;

R⁵selected from hydrogen, C₁-C₆Alkoxy and halogen;

R⁶selected from fused bicyclic ring C₃-C₁₄Carbocyclyl and fused bicyclic 3-14 membered heterocyclyl wherein each such substituent is optionally independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KSubstituted with one or more substituents of (a);

each R^EIndependently selected from halogen, nitro, hydroxy, oxo and amino, wherein:

amino optionally substituted by one or two C ₁-C₆Alkyl substitution;

each R^FIs C₁-C₆An alkyl group, wherein:

each of said substituents being optionally substituted with one or more substituents independently selected from amino and aminosulfonyl, wherein:

amino is optionally independently selected from C₁-C₆Alkyl and C₁-C₆Substituted with an alkylsulfonyl group;

each R^GIs a 5-6 membered heterocyclyl wherein:

each of said substituents being optionally substituted by one or more C₁-C₆Alkyl substitution;

each R^HIs C₁-C₆An alkoxy group;

each R^IIs aminocarbonyl, wherein:

aminocarbonyl is optionally independently selected from C₁-C₆Alkyl and C₁-C₆Alkylsulfonyl substituted with one or two substituents;

each R^JIndependently selected from C₁-C₆Alkylcarbonylamino, C₁-C₆Alkylsulfonylamino group, C₁-C₆Alkoxycarbonylaminoimino and C₁-C₆An alkylsulfonylaminoimino group, wherein:

the amino moiety of said substituent being optionally substituted by C₁-C₆Alkylsulfonyl substitution; and

each R^KIndependently selected from aminosulfonyl and C₁-C₆An alkylsulfonyl group, wherein:

aminosulfonyl optionally substituted by one or two C₁-C₆Alkyl substitution.

2. A compound or salt according to claim 1, whereinIs a carbon-carbon single bond.

3. The compound or salt of claim 1, wherein R⁴Is selected from C₁-C₄Alkyl radical, C₃-C₁₄Carbocyclyl and 5-6 membered heterocyclyl.

4. The compound or salt of claim 1, wherein R⁴Selected from halogen, tert-butyl, C₃-C₁₄Carbocyclyl and 5-6 membered heterocyclyl.

5. The compound or salt of claim 1, wherein R⁴Selected from tert-butyl, C₃-C₁₄Carbocyclyl and 5-6 membered heterocyclyl.

6. The compound or salt of claim 1, wherein R⁴Is selected from C₁-C₆An alkyl group.

7. The compound or salt of claim 1, wherein R⁴Selected from tert-butyl.

8. The compound or salt of claim 1, wherein R⁵Selected from hydrogen, methoxy and halogen.

9. The compound or salt of claim 1, wherein R⁵Selected from methoxy.

10. The compound or salt of claim 1, wherein R⁶Is a fused bicyclic ring C₃-C₁₄A carbocyclic group selected from the group consisting of naphthyl, dihydronaphthyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl, decahydronaphthyl, indenyl, indanyl, hexahydroindenyl, and octahydroindenyl.

11. The compound or salt of claim 1, wherein R⁶Is a fused bicyclic ring C₃-C₁₄A carbocyclic group selected from the group consisting of naphthyl, dihydronaphthyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl, and decahydronaphthyl.

12. The compound or salt of claim 1, wherein R ⁶Is a fused bicyclic ring C₃-C₁₄A carbocyclic group selected from indenyl, indanyl, hexahydroindenyl and octahydroindenyl.

13. The compound or salt of claim 1, wherein R⁶Is naphthyl.

14. The compound or salt of claim 1, wherein R⁶Is an indenyl group.

15. The compound or salt of claim 1, wherein R⁶Is a fused bicyclic 3-14 membered heterocyclic group selected from:

X⁵、X⁶and X⁷Independently selected from N and c (h);

X⁸selected from N (H), O and S;

X¹⁹、X²⁰and X²¹One or more of (a) is N, the remainder are c (h);

X²²、X²³、X²⁴and X²⁵One or more of (a) is N, the remainder are c (h);

X⁴⁰、X⁴¹and X⁴²Independently selected from N and c (h);

X⁴³、X⁴⁴and X⁴⁵One is selected from N (H), O and S, the other two are C (H)₂；

X⁵⁶、X⁵⁷And X⁵⁸Independently selected from N and c (h);

X⁵⁹selected from N (H), O and S;

X⁷³、X⁷⁴、X⁷⁵and X⁷⁶One or more of (a) is N, the remainder are c (h); and

X⁷⁷and X⁷⁸One of N (H) and the other of C (H)₂。

16. The compound or salt of claim 15, wherein:

X⁵、X⁶and X⁷Is C (H);

X¹⁹、X²⁰and X²¹One is N;

X²²、X²³、X²⁴and X²⁵One is N;

X⁴⁰、X⁴¹and X⁴²Is C (H); and

X⁵⁶、X⁵⁷and X⁵⁸Is C (H).

17. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl and fused bicyclic 3-14 membered heterocyclyl wherein each such substituent is independently selected from R ^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

18. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl and fused bicyclic 3-14 membered heterocyclyl wherein each such substituent is independently selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

19. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl and fused bicyclic 3-14 membered heterocyclyl wherein each such substituent is independently selected from R^E、R^FAnd R^JOne and two ofOr three substituents.

20. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

21. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl independently selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with one, two or three substituents.

22. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl independently selected from R^E、R^FAnd R^JIs substituted with one, two or three substituents.

23. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C ₃-C₁₄Carbocyclyl independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or two substituents.

24. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl independently selected from R^E、R^FAnd R^JIs substituted with one or two substituents.

25. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s).

26. The compound or salt of claim 1, wherein R⁶Selected from fused bicyclic ring C₃-C₁₄Carbocyclyl selected from R^FAnd R^JIs substituted with the substituent(s).

27. The compound or salt of claim 1, wherein R⁶Is naphthyl, which is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or two substituents.

28. The compound or salt of claim 1, wherein R⁶Is naphthyl, which is independently selected from R^E、R^FAnd R^JIs substituted with one or two substituents.

29. The compound or salt of claim 1, wherein R⁶Is naphthyl, which is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s).

30. The compound or salt of claim 1, wherein R⁶Is naphthyl, which is selected from R^FAnd R^JIs substituted with the substituent(s).

31. The compound or salt of claim 1, wherein R⁶Is naphthyl, which is substituted by R ^JAnd (4) substitution.

32. The compound or salt of claim 1, wherein R⁶Is an indenyl group, which is independently selectedFrom R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or two substituents.

33. The compound or salt of claim 1, wherein R⁶Is indenyl, which is independently selected from R^E、R^FAnd R^JIs substituted with one or two substituents.

34. The compound or salt of claim 1, wherein R⁶Is indenyl, which is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s).

35. The compound or salt of claim 1, wherein R⁶Is indenyl, which is selected from R^FAnd R^JIs substituted with the substituent(s).

36. The compound or salt of claim 1, wherein R⁶Is an indenyl group, which is substituted by R^FAnd (4) substitution.

37. The compound or salt of claim 1, wherein R^EIndependently selected from halogen, nitro, hydroxy, oxo and amino.

38. The compound or salt of claim 1, wherein R^FIndependently selected from C₁-C₆Alkyl substituted by amino, wherein the amino is C₁-C₆Alkylsulfonyl substitution.

39. The compound or salt of claim 1, wherein R^FIs a methylsulfonylaminomethyl group.

40. As claimed inA compound or salt of claim 1 wherein each R is^JIndependently selected from C₁-C₆An alkylsulfonylamino group.

41. The compound or salt of claim 1 wherein each R ^JIs a methylsulfonylamino group.

42. The compound or salt of claim 1, wherein:

R⁴selected from halogen, C₁-C₄Alkyl radical, C₃-C₁₄-carbocyclyl and 5-6 membered heterocyclyl, wherein:

(a)C₁-C₄-alkyl is optionally independently selected from halogen, oxo, hydroxy, C₁-C₆Up to three substituents of alkoxy and trimethylsilyl, and

(b)C₃-C₁₄-carbocyclyl and 5-6 membered heterocyclyl are optionally independently selected from C₁-C₆Alkyl, halogen and C₁-C₆Alkylsulfonylamino substituted with one or two substituents; and

R⁵selected from hydrogen, C₁-C₆Alkoxy and halogen.

43. The compound or salt of claim 1, wherein:

R⁴is a tert-butyl group; and

R⁵is methoxy.

44. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵selected from hydrogen, methoxy and halogen; and

R⁶is naphthyl, which is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or two substituents.

45. The compound or salt of claim 1, wherein:

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is naphthyl, which is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s).

46. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵selected from hydrogen, methoxy and halogen; and

R⁶Is indenyl, which is independently selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with one or two substituents.

47. The compound or salt of claim 1, wherein:

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is indenyl, which is selected from R^E、R^F、R^G、R^H、R^I、R^JAnd R^KIs substituted with the substituent(s).

48. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is naphthyl, which is independently selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with one or two substituents.

49. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is by R^JSubstituted naphthyl.

50. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is indenyl, which is independently selected from R^E、R^F、R^I、R^JAnd R^KIs substituted with one or two substituents.

51. The compound or salt of claim 1, wherein:

R⁶selected from fused bicyclic 3-14 memberedHeterocyclyl and fused bicyclic ring C₃-C₁₄Carbocyclyl wherein each such substituent is selected from R^FAnd R^JSubstituted with the substituent(s);

R^Fis C₁-C₆Alkylsulfonylamino C₁-C₆An alkyl group; and

R^Jis C₁-C₆An alkylsulfonylamino group.

52. The compound or salt of claim 1, wherein:

Is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is by R^JSubstituted naphthyl; and

R^Jis C₁-C₆An alkylsulfonylamino group.

53. The compound or salt of claim 1, wherein:

is a carbon-carbon double bond;

R⁴is a tert-butyl group;

R⁵is a methoxy group; and

R⁶is by R^FA substituted indenyl group; and

R^Fis C₁-C₆Alkylsulfonylamino C₁-C₆An alkyl group.

54. The compound or salt of claim 1, wherein the substituted fused bicyclic ring C₃-C₁₄The carbocyclic group is selected from naphthyl, dihydronaphthyl, tetrahydronaphthylHexahydronaphthyl, octahydronaphthyl, decahydronaphthyl, indenyl, indanyl, hexahydroindenyl and octahydroindenyl.

55. The compound or salt of claim 1 wherein the compound corresponds in structure to formula IB-L0:

56. the compound or salt of claim 55, wherein R⁴Is a tert-butyl group.

57. The compound or salt of claim 55, wherein R⁵Is methoxy.

58. The compound or salt of claim 55, wherein R⁶Is a fused bicyclic ring C₃-C₁₄Carbocyclyl selected from R^FAnd R^JIs substituted with the substituent(s).

59. The compound or salt of claim 58, wherein the fused bicyclic ring C₃-C₁₄Carbocyclyl is naphthyl.

60. The compound or salt of claim 58, wherein R ^JIs a methylsulfonylamino group.

61. The compound or salt of claim 58, wherein R^FIs a methylsulfonylaminomethyl group.

A crystalline form of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide, and salts thereof, selected from:

an X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide alcohol solvate having peaks at 8.3 + -0.2, 9.7 + -0.2, 10.0 + -0.2, 10.6 + -0.2, 13.6 + -0.2, 17.2 + -0.2, 17.5 + -0.2, 19.2 + -0.2, 19.4 + -0.2, 22.7 + -0.2, 26.9 + -0.2 and 29.4 + -0.22 theta °;

an X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide solvate having peaks at 5.3 + -0.2, 8.3 + -0.2, 9.7 + -0.2, 10.5 + -0.2, 13.8 + -0.2, 17.2 + -0.2, 17.7 + -0.2, 19.1 + -0.2, 19.5 + -0.2, 22.0 + -0.2, 22.8 + -0.2 and 27.2 + -0.22 theta °;

an X-ray powder diffraction pattern comprising crystalline ethyl N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide acetate solvates having peaks at 7.9 ± 0.2, 9.3 ± 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 13.7 ± 0.2, 17.4 ± 0.2, 18.7 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 28.2 ± 0.2, 38.5 ± 0.2 and 44.7 ± 0.22 Θ °;

An X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide 2-propanol solvate having peaks at 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 16.3 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2 and 28.0 ± 0.22 Θ °;

a crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methansulfonamide solvate comprising peaks at 8.4 + -0.2, 9.7 + -0.2, 10.1 + -0.2, 13.5 + -0.2, 13.8 + -0.2, 17.4 + -0.2, 19.3 + -0.2, 19.6 + -0.2 and 27.1 + -0.22 theta °;

an X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide 1-propanol solvate having peaks at 8.2 ± 0.2, 9.3 ± 0.2, 10.1 ± 0.2, 10.5 ± 0.2, 15.7 ± 0.2, 16.2 ± 0.2, 18.4 ± 0.2, 18.6 ± 0.2, 19.3 ± 0.2, 21.0 ± 0.2, 21.6 ± 0.2 and 22.8 ± 0.22 Θ °;

a powder X-ray diffraction pattern comprising solvent-free crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide with peaks at 6.2 ± 0.2, 7.9 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 14.9 ± 0.2, 16.2 ± 0.2, 18.3 ± 0.2, 19.8 ± 0.2 and 26.5 ± 0.22 Θ °;

Crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide hydrate having peaks at 6.4 + -0.2, 12.7 + -0.2, 12.9 + -0.2, 14.1 + -0.2, 15.7 + -0.2, 17.2 + -0.2, 17.5 + -0.2, 17.9 + -0.2, 18.9 + -0.2, 21.2 + -0.2, 24.4 + -0.2 and 25.0 + -0.22 theta °;

a mode A crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt having an X-ray powder diffraction pattern comprising peaks at 4.6 + -0.2, 10.4 + -0.2, 12.0 + -0.2, 15.6 + -0.2, 16.0 + -0.2, 18.6 + -0.2, 22.8 + -0.2, 23.3 + -0.2, 23.9 + -0.2 and 28.3 + -0.22 theta °;

a powder X-ray diffraction pattern comprising mode B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt at peaks at 5.4 + -0.2, 10.8 + -0.2, 14.4 + -0.2, 16.3 + -0.2, 17.0 + -0.2, 18.8 + -0.2, 19.2 + -0.2, 19.6 + -0.2, 21.6 + -0.2, 22.1 + -0.2, 23.7 + -0.2, 28.8 + -0.2, 29.1 + -0.2 and 31.8 + -0.22 theta °;

mode C crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt having an X-ray powder diffraction pattern comprising peaks at 5.0 + -0.2, 12.0 + -0.2, 17.5 + -0.2, 17.8 + -0.2, 18.8 + -0.2 and 22.7 + -0.22 theta °;

Crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt having peaks at 4.8 + -0.2, 9.6 + -0.2, 10.5 + -0.2, 13.0 + -0.2, 14.6 + -0.2, 15.4 + -0.2, 16.8 + -0.2, 22.7 + -0.2, 23.0 + -0.2 and 23.3 + -0.22 theta DEG in an X-ray powder diffractogram;

an X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monopotassium salt at peaks at 5.0 + -0.2, 9.9 + -0.2, 11.3 + -0.2, 13.3 + -0.2, 16.9 + -0.2, 18.1 + -0.2, 19.1 + -0.2, 20.0 + -0.2, 21.1 + -0.2, 21.5 + -0.2, 23.5 + -0.2, 24.8 + -0.2 and 25.7 + -0.22 theta °;

a pattern A crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monocholine salt having peaks at 10.9 + -0.2, 12.1 + -0.2, 13.0 + -0.2, 13.4 + -0.2, 13.6 + -0.2, 15.5 + -0.2, 17.0 + -0.2, 17.8 + -0.2, 18.3 + -0.2, 19.5 + -0.2, 19.7 + -0.2 and 21.9 + -0.22 theta °;

a pattern B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methane sulfonamide monocholinergic salt having peaks at 8.0 ± 0.2, 9.4 ± 0.2, 11.0 ± 0.2, 13.0 ± 0.2, 13.3 ± 0.2, 13.7 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 18.3 ± 0.2, 18.9 ± 0.2, 19.8 ± 0.2, 21.8 ± 0.2 and 22.1 ± 0.22 Θ °; and

An X-ray powder diffraction pattern comprising crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulphonyldicholine salt having peaks at 8.6 + -0.2, 11.0 + -0.2, 12.9 + -0.2, 17.0 + -0.2, 17.5 + -0.2, 18.9 + -0.2, 19.8 + -0.2, 21.9 + -0.2 and 22.1 + -0.22 theta deg.

63. crystalline forms of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide and salts thereof, selected from:

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide ethanolate having an X-ray powder diffraction pattern substantially as shown in figure 1;

a crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide solvate having an X-ray powder diffraction pattern substantially as shown in FIG. 3;

crystalline ethyl N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in figure 4;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide 2-propanol solvate having an X-ray powder diffraction pattern substantially as shown in FIG. 5;

Crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methansulfonamide methanol solvate having an X-ray powder diffraction pattern substantially as shown in FIG. 6;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide 1-propane solvate having an X-ray powder diffraction pattern substantially as shown in FIG. 7;

solvent-free crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in FIG. 8;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in FIG. 9;

mode A crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, having an X-ray powder diffraction pattern substantially as shown in FIG. 10;

mode B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt having an X-ray powder diffraction pattern substantially as shown in figure 12;

Mode C crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide monosodium salt having an X-ray powder diffraction pattern substantially as shown in FIG. 14;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt having an X-ray powder diffraction pattern substantially as shown in FIG. 15;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monopotassium salt having an X-ray powder diffraction pattern substantially as shown in FIG. 17;

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide choline salt, pattern a having an X-ray powder diffraction pattern substantially as shown in figure 19;

form B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulfonamide choline salt having an X-ray powder diffraction pattern substantially as shown in FIG. 21; and

crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-phenyl) naphthalen-2-yl) methanesulphonyldicholine salt having an X-ray powder diffraction pattern substantially as shown in figure 23.

64. A compound or salt selected from:

n- (6- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinolin-2-yl) methanesulfonamide;

(E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide;

n- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-5-yl) methanesulfonamide;

1- (3-tert-butyl-4-methoxy-5- (6-nitrobenzo [ d ] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4(1H, 3H) -dione;

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-6-yl) methanesulfonamide;

1- (3-tert-butyl-4-methoxy-5- (5-nitrobenzo [ d ] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4(1H, 3H) -dione;

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] oxazol-5-yl) methanesulfonamide;

1- (3- (benzo [ d ] thiazol-2-yl) -5-tert-butyl-4-methoxyphenyl) dihydropyrimidine-2, 4(1H, 3H) -dione;

N- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-benzo [ d ] imidazol-5-yl) methanesulfonamide;

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-6-yl) methanesulfonamide;

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-5-yl) methanesulfonamide;

1- (3-tert-butyl-4-methoxy-5- (naphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione;

1- (3-tert-butyl-4-methoxy-5- (6-methoxynaphthalen-2-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide;

(E) -N' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) -2, 3-dihydro-1H-indene-1-ylidene) methanesulfonyl hydrazide;

n- (6- (3-bromo-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (5-methylfuran-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-3-yl) phenyl) naphthalen-2-yl) methanesulfonamide;

N- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-biphenyl-3-yl) naphthalen-2-yl) methanesulfonamide;

n- (6- (3' -chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxybiphenyl-3-yl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (5-methylthiophen-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan-2-yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (1-methoxy-2-methylpropan-2-yl) phenyl) naphthalen-2-yl) methanesulfonamide;

2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) -2-methylpropionic acid methyl ester;

2- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) -2-methylpropionic acid;

methyl 5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) benzoate;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- ((trimethylsilyl) ethynyl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (methylsulfonyl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (6- (methylsulfonylamino) naphthalen-2-yl) phenyl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (trifluoromethyl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (perfluoroethyl) phenyl) naphthalen-2-yl) methanesulfonamide;

(E) -N' - (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide;

(E) -N' - (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) methanesulfonyl hydrazide;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-ethoxyphenyl) naphthalen-2-yl) methanesulfonamide;

n- (6- (3-tert-butyl-2-chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) naphthalen-2-yl) methanesulfonamide;

n- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] isoxazol-3-yl) methyl) methanesulfonamide;

2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-ylidene) hydrazinecarboxylic acid methyl ester;

1- (3-tert-butyl-4-methoxy-5- (1-oxoisoindolin-5-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione;

n- (2- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) propan-2-yl) methanesulfonamide;

n- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide;

n- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1, 2, 3, 4-tetrahydroisoquinolin-6-yl) methanesulfonamide;

N- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) isoindolin-5-yl) methanesulfonamide;

n' - (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methanesulfonyl hydrazide;

1- (3-tert-butyl-5- (1-hydroxy-2, 3-dihydro-1H-inden-5-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione;

1- (3-tert-butyl-5- (2- (2, 5-dimethyl-1H-pyrrol-1-yl) benzo [ d ] thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione;

1- (3- (2-aminobenzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxy-phenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-2-yl) methanesulfonamide;

1- (3- (benzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ d ] thiazol-2-yl) acetamide;

1- (3-tert-butyl-4-methoxy-5- (2- (propylamino) benzo [ d ] thiazol-6-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione;

1- (3-tert-butyl-4-methoxy-5- (3-methylbenzofuran-6-yl) phenyl) -pyrimidine-2, 4(1H, 3H) -dione;

n- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzofuran-3-yl) methyl) methanesulfonamide;

n- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-methyl-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

n- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methanesulfonamide;

n- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide;

n- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-2-yl) phenyl) -1H-inden-3-yl) methyl) methanesulfonamide;

n- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-3-yl) phenyl) -1H-inden-3-yl) methyl) methanesulfonamide;

N- ((6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide;

1- (3-tert-butyl-4-methoxy-5- (1- (methylsulfonyl) indolin-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinoxalin-2-yl) methanesulfonamide;

n- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methanesulfonamide;

n- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -N- (methylsulfonyl) -2, 3-dihydro-1H-indene-1-carboxamide;

1- (3- (2-aminobenzo [ d ] thiazol-6-yl) -5-tert-butyl-4-methoxy-phenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide;

(S) -N- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide;

(R) -N- (2- (5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) propan-2-yl) methanesulfonamide;

(S) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

(R) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

(S) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

(R) -N- ((5- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluoro-2, 3-dihydro-1H-inden-1-yl) methyl) methanesulfonamide;

n- (6- (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3-tert-pentylphenyl) naphthalen-2-yl) methanesulfonamide;

n- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) -N-methylmethanesulfonamide;

n- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-2-yl) methyl) methanesulfonamide;

N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) benzo [ b ] thiophen-3-yl) methyl) -N-methylmethanesulfonamide;

n- (2- (3-tert-butyl-5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-benzo [ d ] imidazol-5-yl) -N- (methylsulfonyl) methanesulfonamide;

n- ((6- (3-tert-butyl-2-chloro-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) phenyl) benzo [ b ] thiophen-3-yl) methyl) methanesulfonamide;

1- (3-tert-butyl-5- (2-chlorobenzo [ d ] thiazol-6-yl) -4-methoxyphenyl) pyrimidine-2, 4(1H, 3H) -dione;

n- (2- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) quinolin-6-yl) methanesulfonamide;

1- (3-tert-butyl-4-methoxy-5- (1-oxo-2, 3-dihydro-1H-inden-5-yl) phenyl) pyrimidine-2, 4(1H, 3H) -dione; and

n, N '- (6, 6' - (5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-1, 3-phenylene) bis (naphthalene-6, 2-diyl)) dimethanesulfonamide.

65. The compound or salt of claim 1, wherein the compound is N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

66. The compound or salt of claim 1, wherein the compound is N- ((6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1H-inden-3-yl) methyl) methanesulfonamide.

67. The salt of claim 1, which is N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide sodium salt.

68. The salt of claim 1, which is N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt.

69. The salt of claim 1, which is N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt.

70. The salt of claim 1, which is N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide potassium salt.

71. A composition comprising (a) one or more compounds and/or salts of claim 1; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents.

72. A composition comprising (a) one or more compounds and/or salts of claim 1 or one or more crystalline forms of claim 62 or 63; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents.

73. Use of one or more compounds and/or salts according to claim 1 or one or more crystalline forms according to claim 62 or 63 in the manufacture of a medicament for inhibiting replication of Hepatitis C Virus (HCV).

74. Use of one or more compounds and/or salts of claim 1 or one or more crystalline forms of claim 62 or 63, and optionally one or more additional therapeutic agents, in the manufacture of a medicament for treating hepatitis c in a mammal in need of such treatment.

75. Use of one or more compounds and/or salts of claim 1 or one or more crystalline forms of claim 62 or 63, and optionally one or more additional therapeutic agents, in the manufacture of a medicament for treating hepatitis c in a human in need of such treatment.

76. The use of claim 74 or 75, wherein the one or more additional therapeutic agents are selected from the group consisting of interferon agents, ribavirin, HCV inhibitors, and HIV inhibitors.

77. A process for preparing a compound or salt of claim 1, wherein the process comprises reacting a compound of formula III with a compound of formula IV in the presence of (I) a copper (I) salt catalyst and (ii) a nitrogen-containing heteroaryl ligand

Wherein R is¹、R²、R³、R⁴And R⁵As defined in claim 1, X¹Is halogen, X²Selected from chlorine, bromine and iodine.

78. The process of claim 77, wherein said process is carried out in the presence of a base.

79. The method of claim 78, wherein said base is selected from the group consisting of potassium, sodium and cesium salts.

80. The method of claim 77, wherein the nitrogen-containing heteroaryl ligand comprises a picolinamide compound corresponding in structure to formula V:

R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶and R¹⁷Independently selected from hydrogen, C_1-4-perfluoroalkyl group, C_1-4-alkoxy, C_1-4Haloalkyl, chlorine and cyano.

81. The method of claim 77, wherein the nitrogen-containing heteroaryl ligand is selected from the group consisting of 8-hydroxyquinoline, 2- (2-pyridyl) -benzimidazole, N- (4-cyano-phenyl) picolinamide, and N- (2-cyanophenyl) picolinamide.

82. The method of claim 77, wherein the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, Cu₂O and CH₃C(O)OCu。

N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide.

Form B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, having an X-ray powder diffraction pattern substantially as shown in figure 12.

85. A composition comprising (a) N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents.

86. A composition comprising (a) mode B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, having an X-ray powder diffraction pattern substantially as shown in figure 12; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents.

87. The composition of any one of claims 85-86 wherein the one or more additional therapeutic agents is selected from the group consisting of an interferon agent, ribavirin, an HCV inhibitor, and an HIV inhibitor.

88. use of N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide in the preparation of a medicament for inhibiting the replication of Hepatitis C Virus (HCV).

89. use of the crystalline form B N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, having an X-ray powder diffraction pattern substantially as shown in figure 12, for the preparation of a medicament for inhibiting replication of Hepatitis C Virus (HCV).

90.N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide and, optionally, one or more additional therapeutic agents in the manufacture of a medicament for the treatment of hepatitis C in a mammal in need of such treatment.

Use of mode B crystalline N- (6- (3-tert-butyl-5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide monosodium salt, having an X-ray powder diffraction pattern substantially as shown in figure 12, and, optionally, one or more additional therapeutic agents, in the preparation of a medicament for the treatment of hepatitis c in a mammal in need of such treatment.

92. The use of any one of claims 90-91, wherein the one or more additional therapeutic agents are selected from the group consisting of interferon agents, ribavirin, HCV inhibitors, and HIV inhibitors.